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Carcinoma, Renal CellPhase 1NCT02014636

Safety and Efficacy Study of Pazopanib and MK 3475 in Advanced Renal Cell Carcinoma (RCC; KEYNOTE-018)

A Phase 1 study testing Pazopanib and MK-3475 in people with Carcinoma, Renal Cell, run by Novartis Pharmaceuticals at 6 sites in 2 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 is an open-label, 2 part study of pazopanib and/or MK 3475 in treatment naïve subjects with advanced RCC. Part 1 consists of a Phase I dose escalation of pazopanib + MK 3475 followed by an expansion cohort to determine the maximum tolerated regimen and the recommended Phase II dose. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Renal Cell
What is being tested?
Pazopanib and MK-3475
Could I receive a placebo?
No, everyone receives an active treatment
How many people
42 participants
Where
6 sitesin 2 countries
Study dates
27 Dec 2013to 27 Feb 2019
Phase
Phase 1
Are there results?
None posted in the registry

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

Who may be able to join

  • Signed written informed consent before performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up
  • Diagnosis of locally advanced or metastatic RCC that is predominantly clear cell histology
  • Must have measurable disease
  • Subject has received no prior systemic therapy
  • A woman is eligible to participate in the study if she is of Non-childbearing potential, has a negative serum pregnancy test within 7 days of the first dose of study treatment, not lactating, and agrees to use adequate contraception during the study until at least 120 days after the last dose of investigational product
  • Eastern Cooperative Oncology Group performance status 0 or 1
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  • Adequate organ function as defined in the protocol
  • Left ventricular ejection fraction >= lower limit of normal as assessed by echocardiogram or multigated acquisition scan
  • In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Who cannot join

  • Subject has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
  • Subject is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study treatment
  • Subject is expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Subject is on any systemic steroid therapy, within one week before the planned date for first dose of study treatment. Subject is on any other form of immunosuppressive medication
  • Subject has a history of a malignancy (other than the disease under treatment in the study) within 5 years before first study treatment administration
  • Central nervous system metastasis
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  • Unable to swallow and retain orally administered medication
  • Subject has interstitial lung disease or a history of pneumonitis
  • Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other Gastrointestinal conditions with increased risk of perforation; history of abdominal fistula, GI perforation, or intra-abdominal abscess within 4 weeks before beginning study treatment
  • Known history of HIV infection or a known history of or is positive for Hepatitis B or Hepatitis C
  • Presence of active infection requiring systemic therapy
  • Corrected QT interval duration prolongation
  • History of any one or more of the following cardiac conditions within the past 6 months: Cardiac angioplasty or stenting; Myocardial infarction; Unstable angina; History of Class III or IV congestive heart failure according to New York Heart Association classification
  • History of cerebrovascular accident within the past 6 months
  • Poorly controlled hypertension
  • History of untreated deep venous thrombosis
  • Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Recent hemoptysis
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage
  • Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
  • Previous severe hypersensitivity reaction to another Monoclonal antibody. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the excipients in pazopanib tablets
  • Has taken any prohibited medications that are listed in the protocol within 14 days of the first dose of study treatment. Subject has received or will receive a live vaccine within 30 days before the first administration of study treatment

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

United States4 sites

  • Novartis Investigative Site

    Boston, Massachusetts, 02115

  • Novartis Investigative Site

    Boston, Massachusetts, 02215

  • Novartis Investigative Site

    Nashville, Tennessee, 37203

  • Novartis Investigative Site

    New York, New York, 10065

Other trials in United States

United Kingdom2 sites

  • Novartis Investigative Site

    London, W1G 6AD

  • Novartis Investigative Site

    Manchester, Lancashire, M20 4BX

Other trials in United Kingdom

About this study

Official title: A Phase I/II Study to Assess the Safety and Efficacy of Pazopanib and MK 3475 in Patients With Advanced Renal Cell Carcinoma

This is an open-label, 2 part study of pazopanib and/or MK 3475 in treatment naïve subjects with advanced RCC. Part 1 consists of a Phase I dose escalation of pazopanib + MK 3475 followed by an expansion cohort to determine the maximum tolerated regimen and the recommended Phase II dose. Part 2 is a randomized 3-arm Phase II study to evaluate the clinical efficacy and safety of pazopanib + MK 3475 as compared to single-agent pazopanib and single-agent MK 3475. The objectives of this Phase I/II study are to test the safety and tolerability of pazopanib in combination with MK 3475, and study the clinical efficacy of pazopanib in combination with MK 3475 in subjects with advanced RCC as compared with single-agent pazopanib and single-agent MK 3475.

Following the Urgent Safety Measure (USM) released on February 09, 2017, the phase II (Part 2) portion of this study will not commence.

Being tested
Pazopanib, MK-3475
Keywords
Pazopanib (GW786034), MK 3475, Renal cell carcinoma
Medical subject headings
Carcinoma, Renal Cell

What participants receive

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

  • PazopanibDrug

    Pazopanib is an orally administered 200 mg tablet available in the dose range of 400 to 800 mg

  • MK-3475Drug

    MK 3475 is an intravenously administered 100 mg/ 4mL solution available in the potential dose range of 1 to 10 mg/kg.

Study groups in NCT02014636
Study groupRoleWhat they receive
Part 1ExperimentalPart 1 is a dose escalation phase in which subjects will receive pazopanib orally and the MK 3475 intravenously. Subjects will be evaluated for a minimum of 8 weeks before the next dose level cohort is enrolled.
Receives: Drug: Pazopanib; Drug: MK-3475
Part 2ExperimentalPart 2 is a randomized phase in which subjects will be enrolled in each treatment arm: Pazopanib monotherapy Pazopanib+MK-3475 MK-3475 monotherapy
Receives: Drug: Pazopanib; Drug: MK-3475

What is being measured

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

  1. Part 1: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs )

    Measured: From the start of study treatment (first dose) and, until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs

  2. Part 1: To determine the dose limiting toxicity (DLT) and maximum tolerated regimen (MTR)

    MTR is defined as the highest dose of pazopanib in combination with the highest dose of MK 3475 at which no more than 1 of 6 subjects experiences a DLT after a minimum of 8 weeks of treatment. DLT is defined as a drug-related AE starting in the first 8 weeks of treatment

    Measured: 8 weeks

  3. Part 1: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays

    Measured: 24 months

  4. Part 1: Change from baseline in laboratory parameters

    Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test

    Measured: Average of 4 years

  5. Part 1: Change from baseline in vital signs

    Vital sign measurements will include heart rate, temperature and blood pressure

    Measured: 30 days after the last dose of study treatment

  6. Part 1: Change from baseline in cardiac parameters

    Cardiac assessments will include Electrocardiogram (ECG) and Echocardiograms (ECHOs)

    Measured: 24 months

  7. Part 1: Incidence and titer of anti MK 3475 antibodies

    Subjects will be monitored for anti-MK 3475 antibodies throughout the study

    Measured: 24 months

  8. Part 2: Progression-free survival (PFS)

    PFS is defined as the interval between the date of randomization and the earlier date of disease progression (using RECIST v1.1) or death due to any cause.

    Measured: Average of 4 years

Secondary outcomes (17)

  1. Part 1: Dose escalation cohorts: pazopanib plasma concentrations and serum MK 3475 concentrations.

    For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects

    Measured: For Pazopanib: before and after the 1st and 2nd dose of MK-3475. For MK-3475: Until 6 months after the last dose of MK-3475

  2. Part 1: Pharmacokinetic (PK) parameters in Expansion cohort

    Area under the plasma concentration-time curve from time 0 to 24 hrs (AUC[0-24], maximum observed concentration (Cmax), tmax, and concentration at 24 hours (C24) of pazopanib; Pre-dose (trough) concentration at the end of the dosing interval (Ctau), and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.

    Measured: For Pazopanib: before and after the 1st and 2nd dose of MK-3475. For MK-3475: Until 6 months after the last dose of MK-3475

  3. Part 1 and Part 2: Overall response rate (ORR)

    Overall response rate is defined as the percentage of subjects, who achieved either a confirmed complete response (CR) or partial response (PR) by RECIST v1.1 and modified RECIST

    Measured: Average of 4 years

  4. Part 1 and Part 2: Clinical benefit rate

    Clinical benefit rate is defined as a confirmed response of CR or PR or at least 6-months stable disease by RECIST v1.1 and modified RECIST.

    Measured: Average of 4 years

  5. Part 1 and Part 2: Time to response

    Time to response is defined for all subjects with a confirmed CR or PR as per RECIST v1.1as the time from randomization until the first documented evidence of CR or PR (whichever status is recorded first)

    Measured: Average of 4 years

  6. Part 1 and Part 2: Duration of response

    Duration of response is defined for all subjects with confirmed CR or PR as the time from the first documented evidence of CR or PR until time of first documented disease progression or death due to any causes, whichever is first by RECIST v1.1 and modified RECIST

    Measured: Average of 4 years

  7. Part 2: PFS by modified RECIST

    Measured: Average of 4 years

  8. Part 1 and Part 2: Progression-free survival rate at 18 months (PFSR18)

    PFSR18 will be calculated based on Kaplan-Meier estimates of Progression-free survival (PFS) at 18 months by RECIST v1.1 and modified RECIST

    Measured: 18 months

  9. Part 2: Overall survival (OS) at 18 months

    Overall survival at 18 months will be summarized based on the Kaplan-Meier method.

    Measured: 18 months

  10. Part 2: Overall survival (OS)

    Overall survival will be summarized using Kaplan-Meier survival curves

    Measured: Average of 4 years

  11. Part 2: Incidence and severity of AEs and SAEs

    Measured: From the start of study treatment (first dose) and, until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs

  12. Part 2: Number of subjects with permanent discontinuation of treatment, dose reductions, interruptions, or delays

    Measured: Average of 4 years

  13. Part 2: Change from baseline in laboratory parameters

    Laboratory assessments include haematology, clinical chemistry, urine, coagulation and thyroid function test

    Measured: Average of 4 years

  14. Part 2: Change from baseline in vital signs

    Vital sign measurements will include heart rate, temperature and blood pressure

    Measured: Average of 4 years

  15. Part 2: Change from baseline in cardiac parameters

    Cardiac assessments will include ECG and ECHOs

    Measured: Average of 4 years

  16. Part 2: Incidence and titer of anti MK 3475 antibodies in patients treated with pazopanib + MK 3475 and single-agent MK 3475

    Subjects will be monitored for anti-MK 3475 antibodies throughout the study

    Measured: Until 6 months after the last dose of MK-3475

  17. Part 2: PK parameters in randomized phase

    For analysis of plasma pazopanib and serum MK 3475 concentrations, blood samples will be collected from all subjects. AUC[0-24], Cmax, tmax, and C24 of pazopanib alone and in combination with MK 3475; Cmax, Ctau, and apparent clearance following oral dosing CL/F of pazopanib will be determined if data permit.

    Measured: For Pazopanib: Until Dose 49 of MK-3475.

Timeline

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

  1. First posted18 Dec 2013 (estimated)
  2. Study start27 Dec 2013
  3. Primary completion27 Feb 2019
  4. Study completion27 Feb 2019

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
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
42 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02014636
Sponsor's protocol ID
200249
Other IDs
KEYNOTE-018, PZP034A2101
Status last verified
Feb 2020
First submitted
12 Dec 2013
Last updated
3 Mar 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided: 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 study testing Pazopanib and MK-3475 in people with Carcinoma, Renal Cell, run by Novartis Pharmaceuticals at 6 sites in 2 countries.

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

Who may be eligible to take part?

The sponsor lists 9 inclusion and 23 exclusion criteria. 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 3 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States, United Kingdom. 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 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.

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

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Part 1: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs ) (time frame: From the start of study treatment (first dose) and, until the post-treatment follow-up visit (at least 30 days after the last dose of investigational product) for AEs, and until 90 days after last dose for SAEs). The study lists 8 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 NCT02014636.

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 3 Mar 2020.

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