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AzTrials

CancerPhase 1/2NCT01750918

BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)

A Phase 1/2 study testing Dabrafenib, Trametinib and Panitumumab in people with Cancer, run by Novartis Pharmaceuticals at 20 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Cancer
What is being tested?
Dabrafenib, Trametinib and Panitumumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
166 participants
Where
20 sitesin 8 countries
Study dates
19 Dec 2012to 18 Jun 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the following criteria

  • Provided written informed consent,
  • Male or female >=18 years of age and able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
  • Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic BRAF V600E mutation positive CRC
  • Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy, defined as patients that derived benefit (disease control based on investigator assessment for >6 months OR partial response [confirmed or unconfirmed] based on RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then subsequently progressed on therapy. The anti-EGFR therapy must have been the most recent therapy and the patient must have progressed based on investigator assessment within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include: a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b. irinotecan/anti-EGFR combo after previously having disease progression (based on investigator assessment) on an irinotecan-containing regimen
  • Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation positive advanced or metastatic colorectal cancer (CRC who are eligible to receive fluoropyrimidine-containing chemotherapy regimen that have experienced documented radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease, having failed or been intolerant to at least one regimen of fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the advanced/metastatic setting. Enrollment in Part 3 may only occur following confirmation of KRAS wild-type cancer.
  • Archival tissue is required; if archival tissue is not available or found to not contain tumor tissue, a fresh biopsy is required.
  • Measurable disease per RECIST version 1.1.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use one of the contraception methods listed in protocol.
  • Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or post-menopausal female defined as 12 months of spontaneous amenorrhea to be verified with a follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing potential and agrees to use one of the contraceptive methods listed in protocol.
  • Female subjects must agree to use contraception from 7 days prior to the first dose of study drug(s) until 6 months after the last dose of panitumumab, until 4 months after the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever is longer. Additionally, women of childbearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug(s).
  • Adequate organ system function as defined in absolute neutrophil count greater than or equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 × 10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN); serum magnesium greater than or equal to the lower limit of normal (LLN); albumin greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left ventricular ejection fraction (LVEF) greater than or equal to the LLN by echocardiography (ECHO) or multigated acquisition scan (MUGA).
  • Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in the study

  • History of prior malignancy, other than colorectal cancer.
  • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
  • Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator's assessment).
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or biologic therapy).
  • Prior exposure to a MEK inhibitor.
  • Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF inhibitor.
  • Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of KRAS-mutation based on previous KRAS-testing. Note: Prospective KRAS testing is not required. However, if the results of previous KRAS testing are known, they must be used in assessing eligibility. KRAS testing will be performed retrospectively for all patients.
  • Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody
  • Received an investigational or approved anti-cancer drug within 4 weeks, or within 5 half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug(s).
  • Part 3: Received more than one prior anti-cancer therapy in the metastatic setting, exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy in the metastatic setting is prohibited.
  • Current use of a prohibited medication or requirement to dose with any of these medications during treatment with study drug(s).
  • Known Hepatitis B, or Hepatitis C infection.
  • Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of study drug(s).
  • Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of study drug(s). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within 2 weeks prior to first dose of study drug(s).
  • Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy, with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that are allowed per inclusion criteria.
  • History of retinal vein occlusion (RVO).
  • Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs. Previous colectomy is acceptable.
  • Subjects with brain metastases are excluded, unless: All known lesions must be previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for >=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants for >=14 days prior to first dose of study drug(s). In addition, for subjects that had brain metastases but currently have no evidence of disease (NED), NED for >=12 weeks is required and must be confirmed by two consecutive MRI or CT scans (using contrast) separated by >=6 weeks, prior to randomization. Enrollment of a subject with brain metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK) Medical Monitor.
  • Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
  • History or evidence of cardiovascular risk including any of the following: LVEF<LLN; A QT interval corrected for heart rate using the Bazett's formula (QTcB;) ≥ 480 milliseconds (msec);.History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30 days prior to randomization are eligible. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization. History or evidence of current >= Class II congestive heart failure as defined by New York Heart Association (NYHA). Treatment refractory hypertension defined as a blood pressure of systolic> 140 millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases
  • Unstable pulmonary embolism, deep vein thrombosis, or other significant arterial/venous thromboembolic event <=30 days before randomization. If on anticoagulation, subject must be on stable therapeutic dose prior to randomization.
  • Subjects with a history of pneumonitis or interstitial lung disease (ILD).
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug(s) or their excipients.
  • Pregnant or lactating female.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Uncontrolled diabetes or other medical condition that may interfere with assessment of toxicity.

Trial locations and contacts

20 sites in 8 countries.

20 sites in 8 countries

United States8 sites

  • Novartis Investigative Site

    Boston, Massachusetts, 02114

  • Novartis Investigative Site

    Boston, Massachusetts, 02215

  • Novartis Investigative Site

    Chapel Hill, North Carolina, 27599

  • Novartis Investigative Site

    Nashville, Tennessee, 37203

  • Novartis Investigative Site

    New York, New York, 10065

  • Novartis Investigative Site

    Philadelphia, Pennsylvania, 19104

  • Novartis Investigative Site

    San Francisco, California, 94115

  • Novartis Investigative Site

    Scottsdale, Arizona, 85259

Other trials in United States

Belgium2 sites

  • Novartis Investigative Site

    Brussels, 1200

  • Novartis Investigative Site

    Leuven, 3000

Other trials in Belgium

France2 sites

  • Novartis Investigative Site

    Paris, 75571

  • Novartis Investigative Site

    Villejuif, 94805

Other trials in France

Italy2 sites

  • Novartis Investigative Site

    Candiolo, 10060

  • Novartis Investigative Site

    Milan, 20162

Other trials in Italy

Japan2 sites

  • Novartis Investigative Site

    Aichi, 464-8681

  • Novartis Investigative Site

    Chiba, 277-8577

Other trials in Japan

Netherlands2 sites

  • Novartis Investigative Site

    Amsterdam, 1066 CX

  • Novartis Investigative Site

    Utrecht, 3584 CX

Other trials in Netherlands

Spain1 site

  • Novartis Investigative Site

    Barcelona, 08035

Other trials in Spain

United Kingdom1 site

  • Novartis Investigative Site

    Birmingham, B15 2TH

Other trials in United Kingdom

About this study

Official title: An Open-Label, Four-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR Antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E Positive Colorectal Cancer and in Subjects With CRC With Secondary Resistance to Prior Anti-EGFR Therapy

This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).

Read the detailed description

Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.

Part 2A:

This was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.

Part 2B:

In this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.

Part 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).

Part 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.

Part 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.

Part 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.

Conditions
Cancer
Being tested
Dabrafenib, Trametinib, Panitumumab, 5-fluorouracil
Keywords
MEK inhibitor, anti-EGFR antibody, colorectal cancer, BRAF inhibitor
Medical subject headings
Neoplasms, Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Also called GSK2118436, DRB436

    Each capsule contains 50 mg or 75 mg of GSK2118436; 50 mg strength capsules are Swedish orange (dark red) opaque hypromellose size 2 capsules and 75 mg strength capsules are pink opaque hypromellose size 1 capsules. The initial dosing regimen will be twice daily (BID) continuous oral daily dosing.

  • TrametinibDrug

    Also called GSK1120212, TMT212

    Each tablet contains 0.5mg or 2.0 mg GSK1120212; 0.5 mg is yellow modified oval biconvex film-coated tablets of size 4.8 mm X 8.9 mm and 2 mg as pink round biconvex film coated tablets;7.5 mm in diameter. The initial dosing regimen will be once daily continuous oral daily dosing.

  • PanitumumabDrug

    Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes.

  • 5-fluorouracilDevice

    5-fluorouracil-based chemotherapy

Study groups in NCT01750918
Study groupRoleWhat they receive
Part 1: Dabrafenib and PanitumumabExperimentalIn Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams [mg] twice daily) and panitumumab (6 milligrams per kilogram [mg/kg] every-2-week [Q2W]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated.
Receives: Drug: Dabrafenib; Drug: Panitumumab
Part 1: Dabrafenib, Trametinib and PanitumumabExperimentalIn Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined.
Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Panitumumab
Part 2: Dabrafenib and panitumumabExperimentalIn Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab
Receives: Drug: Dabrafenib; Drug: Panitumumab
Part 2: Dabrafenib, Trametinib and PanitumumabExperimentalIn Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab.
Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Panitumumab
Part 4a: Trametinib and PanitumumabExperimentalSubject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W
Receives: Drug: Trametinib; Drug: Panitumumab
Part 4b: Trametinib and PanitumumabExperimentalIn Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E).
Receives: Drug: Trametinib; Drug: Panitumumab
Part 3a: Dabrafenib and PanitumumabExperimentalSubjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.
Receives: Drug: Dabrafenib; Drug: Panitumumab
Part 3b: Dabrafenib, Trametinib and PanitumumabExperimentalSubjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2.
Receives: Drug: Dabrafenib; Drug: Trametinib
Part 3c: Chemotherapy comparatorExperimentalSubjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy
Receives: Device: 5-fluorouracil

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Adverse Events

    The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.

    Measured: From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months

  2. Overall Response Rate (ORR)

    Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) was used for efficacy based on radiological assessment of tumor burden: CR = Complete Response, disappearance of all target lesions; PR = Partial Response, >=30% decrease in the sum of the longest diameter of target lesions; PD = progressive disease, >=20% increase in sum of target lesions and/or presence of new lesions and/or substantial increase in non-target lesion; SD = stable disease, response not meeting CR or PR or PD; ORR = overall response rate, defined as CR+PR

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

  3. Part 3: Progression Free Survival (PFS)

    Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

Secondary outcomes (33)

  1. Duration of Response (DoR)

    Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

  2. Progression Free Survival (PFS)

    Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

  3. Overall Survival (OS)

    Overall Survival (OS) was defined as the time to death due to any cause.

    Measured: From study treatment start date until date of of death from any cause, assessed up to approximately 90 months

  4. Cmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  5. Cmax of Trametinib in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  6. Tmax of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  7. Tmax of Trametinib in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  8. AUC[0-8] of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8 (Dabrafenib derived metabolites), Week 12, Week 16, Week 20

  9. AUC[0-8] of Trametinib in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) 8 hours (AUC[0-8]) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  10. Ctau of Dabrafenib and Derived Metabolites in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Dabrafenib and derived metabolites were listed and summarized using descriptive statistics.

    Measured: Day 15, Week 8, Week 12, Week 16, Week 20

  11. Ctau of Trametinib in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 15, Week 8, Week 12, Week 16, Week 20

  12. Ctau of Panitumumab in the Triple Combination (D+T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.

    Measured: Day 15, Week 4, Week 8, Week 12, Week 16, Week 20

  13. Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) of Dabrafenib estimated with the PopPK model are summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  14. Effect of Combination With Trametinib on Apparent Maximum Inducible Clearance at Steady State of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The effect of combination with trametinib on apparent maximum inducible clearance at steady state (CLIND,SS/F) (CLCOMBO) of Dabrafenib estimated with the PopPK model is summarized in this record.

    The parameter in question is a covariate that describes the effect of Effect of combination with trametinib on apparent maximum inducible clearance: the number denoting the effect means that the including trametinib will decrease the apparent maximum inducible clearance as opposed to when dabrafenib is administered alone.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  15. Oral Volume of Distribution (V/F) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib of Dabrafenib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  16. Absorption Rate Constant (Ka) of Dabrafenib in the Triple Combination (D+T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  17. Cmax of Trametinib in the Double Combination (T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Maximum observed concentration (Cmax) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 12, Week 20

  18. Tmax of Trametinib in the Double Combination (T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Time of occurrence of Cmax (tmax) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 12, Week 20

  19. AUC[0-t] of Trametinib in the Double Combination (T+P)

    Serial blood samples will be collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples will be collected every 4 weeks up to and including Week 20 on study. Area under the concentration-time curve from zero (pre-dose) the time of the last quantifiable concentration (AUC[0-t]) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 1, Day 15, Week 12, Week 20

  20. Ctau of Trametinib in the Double Combination (T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Trametinib was listed and summarized using descriptive statistics.

    Measured: Day 15, Week 8, Week 12, Week 16, Week 20

  21. Ctau of Panitumumab in the Double Combination (T+P)

    Serial blood samples were collected pre-dose and post-dose on Day 1, Day 15 and pre-dose on Day 21 in the first 28 days of dosing. In the continuation period, blood samples were collected every 4 weeks up to and including Week 20 on study. Pre-dose (trough) concentration at the end of the dosing interval (Ctau) of Panitumumab was listed and summarized using descriptive statistics.

    Measured: Day 15, Week 8, Week 12, Week 16, Week 20

  22. Apparent Base Clearance (CL0/F) and Apparent Maximum Inducible Clearance at Steady State (CLIND,SS/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The apparent base clearance (CL0/F) and apparent maximum inducible clearance at steady state (CLIND,SS/F) dabrafenib estimated with the PopPK model are summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  23. Oral Volume of Distribution (V/F) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The oral volume of distribution (V/F) of Dabrafenib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  24. Absorption Rate Constant (Ka) of Dabrafenib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Dabrafenib can be described using a two-compartment model with a delayed 1st order absorption (Alag1, Ka) and an inducible elimination (CL/F) that consists of a base clearance (constant over time, CL0/F) and a dose- and time-dependent inducible clearance (CLind/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of dabrafenib. The absorption rate constant (Ka) of Dabrafenib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  25. Apparent Clearance (CL/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent clearance (CL/F) of Trametinib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  26. Apparent Central Volume (V/F) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The apparent central volume (V/F) of Trametinib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  27. Absorption Rate Constant 1 (Ka1) and Absorption Rate Constant 2 (Ka2) of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The absorption rate constant 1 (Ka1) and absorption rate constant 2 (Ka2) of Trametinib estimated with the PopPK model are summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  28. Time When Ka1 Transitions to Ka2 of Trametinib in the Double Combination (T+P) Estimated With a PopPK Model

    The population pharmacokinetic (PopPK) model of Trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination (CL/F). The PopPK analysis examined the influence of demographics (i.e., weight) on the pharmacokinetics of trametinib. The time when Ka1 transitions to Ka2 of Trametinib estimated with the PopPK model is summarized in this record.

    Measured: Day 1, Day 15, Week 8, Week 12, Week 16, Week 20

  29. Change in Levels of Proteins/Ribonucleic Acid (RNA)

    H-score or "Histo-score" measures cell membrane immunohistochemistry staining intensity in a fixed field. Membrane staining is categorized as 1+, 2+, or 3+. Minimum score is 0, maximum score is 300 (no subscale values are reported). H-score values themselves are not considered to be better or worse - measurements for levels of proteins/ribonucleic acid (RNA) are surrogate for MAPK pathway activity. Low values = low pathway activity. High values = high pathway activity. Changes in mean phosphorylated-ERK (pERK) and phosphorylated ribosomal protein S6 (pS6) H-score from baseline indicate changes in MAPK pathway activity that may be associated with treatment arms. A positive change from baseline suggests increased pathway activity. A negative change from baseline suggests decreased pathway activity. Total score is calculated as follows: [1 x (% cells 1+) + 2 x (% cells 2+) + 3 x (% cells 3+)].

    Measured: Baseline, Day 15

  30. Part 3: Overall Response Rate (ORR)

    Overall Response Rate (ORR) was defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) using RECIST 1.1

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

  31. Part 3: Duration of Response (DoR)

    Duration of Response (DoR) was defined as the time from the first documented occurrence of response (PR or CR) until the date of the first documented progression based on RECIST v1.1 or death.

    Measured: From study treatment start date until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 90 months

  32. Part 3: Overall Survival (OS)

    Overall Survival (OS) was defined as the time to death due to any cause.

    Measured: From study treatment start date until date of of death from any cause, assessed up to approximately 90 months

  33. Part 3: Number of Participants With Treatment Emergent Adverse Events

    The distribution of adverse events (AE) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

    Measured: From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Dec 2012 (estimated)
  2. Study start19 Dec 2012
  3. Primary completion18 Jun 2020
  4. Study completion18 Jun 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
The original intention of the study was to include a randomized phase 2 portion of the study as a "Part 3"; however, a preliminary analysis did not meet predetermined criteria for efficacy. As a result, Part 3 of the study was not initiated.
Masking
None (open label)
Enrolment
166 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01750918
Sponsor's protocol ID
116833
Other IDs
CDRB436C2201, 2012-004802-81
Status last verified
Sep 2021
First submitted
6 Dec 2012
Last updated
29 Oct 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: This product has been acquired by Novartis Pharmaceuticals. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Dabrafenib, Trametinib and Panitumumab in people with Cancer, run by Novartis Pharmaceuticals at 20 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites in United States, Belgium, France, Italy, Japan and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 29 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Adverse Events (time frame: From study treatment start date till 30 days safety follow-up, assessed up to approximately 90 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01750918.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2021.

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