Uveal MelanomaPhase 1/2NCT04589832
Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma
A Phase 1/2 study testing PAC-1 and Entrectinib in people with Uveal Melanoma, run by Arkadiusz Z. Dudek, MD at 1 site in United States.
Trial summary
Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after every 2 cycles. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Uveal Melanoma
- What is being tested?
- PAC-1 and Entrectinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Jan 2021to 24 Jun 2022
- 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
Who may be able to join
- Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be willing and able to provide written informed consent for this trial.
- Age ≥ 18 years at the time of consent.
- Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC manual edition 8.
- One or more lesions that could be accurately measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 1).
- Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 14 days prior to registration.
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- Leukocytes ≥ 2,000 µ/l
- Absolute Neutrophil Count (ANC) ≥ 1,500 K/mm3
- Platelets ≥ 100,000/µl
- Hemoglobin (Hgb) ≥ 9 g/dL
- Serum Creatinine ≤ 1.5 x ULN
- Calculated creatinine clearance ≥ 40 mL/min
- Total Bilirubin ≤ 1.5 mg/dL
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN
- Alkaline Phosphatase ≤ 2.5 × ULN
- Partial Thromboplastin Time (PTT) < 1.5 × ULN
- Subjects must have archival tissue (metastatic disease preferred) available or undergo a biopsy prior to Cycle 1 Day 1 of treatment. Subjects that do not have archival tissue or cannot undergo a biopsy are not eligible for the study.
- Prior therapy is allowed but must have been completed 21 days prior to initiation of protocol therapy and all toxicities must be < Grade 2.
- Palliative radiation must have been completed 2 weeks prior to the initiation of study therapy.
- Patient with known brain metastases must have been treated at least 2 weeks prior to enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be receiving a supra-physiologic dose of steroids (>10 mg prednisone daily or equivalent).
- Women must not be pregnant or breastfeeding. All women of childbearing potential (WOCBP) must have a blood human chorionic gonadotrophin (hCG) test or urine hCG test within 2 weeks prior to registration to rule out pregnancy.
- Women of childbearing potential (WOCBP) must agree to use contraception as outlined in the protocol from the time of informed consent, during the study and for 3 months after the last dose of study drug(s). Abstinence from heterosexual intercourse is an acceptable form of contraception. Women of childbearing potential are those who have not been surgically sterilized or have not been free of menses >1 year
- Male patients who are sexually active with WOCBP must agree to use contraception as outlined in the protocol from the time of initiation of study treatment, during the study and for 3 months after the last dose of study drug(s). Abstinence from heterosexual intercourse is an acceptable form of contraception.
- The participant is capable of understanding and complying with the protocol and has signed informed consent document.
Who cannot join
- Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).
- Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
- Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. For patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is only eligible if they are negative for HBV DNA.
- Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. NOTE: Radiation-induced lung disorders are not included in this exclusion criterion.
- History of retinal pigmented epithelial detachment, central serous retinopathy, or retinal vein occlusion in the unaffected eye; or intraocular pressure 21 mmHg or uncontrolled glaucoma (irrespective of intraocular pressure) in the unaffected eye.
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- History of uncontrolled seizures.
- History of ataxia.
- Allergies and adverse drug reaction: History of allergy to study drug components.
- Thromboembolic events requiring therapeutic anticoagulation. Concomitant anticoagulation with oral anticoagulants (warfarin, direct thrombin or factor Xa inhibitors), platelet inhibitors (e.g. Clopidogrel, high dose aspirin) is prohibited. Low-dose aspirin (<100 mg/day), low-dose warfarin (<1 mg/day) and prophylactic low molecular weight heparin (LMWH) or similar agent are permitted.
- History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study.
- History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds from ECGs performed at least 24 hours apart).
- History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome).
- Cardiovascular disorders including unstable angina pectoris, clinically-significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack [TIA], or other ischemic event) within 6 months prior to registration.
- Active infection requiring intravenous systemic treatment.
- Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration.
- Known uncontrolled, symptomatic brain metastasis or cranial epidural disease.
- Known additional malignancies which require systemic treatment.
- Inability to swallow intact tablets.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the sponsor-investigator.
Trial locations and contacts
1 site in 1 country.
United States1 site
HealthPartners Institute Regions Cancer Care Center
Minneapolis, Minnesota, 55440
About this study
Official title: Phase 1B/2 Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma
Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after every 2 cycles. Treatment will continue until disease progression based on RECIST criteria or intolerable toxicity.
- Conditions
- Uveal Melanoma
- Being tested
- PAC-1, Entrectinib
- Keywords
- uveal melanoma
- Medical subject headings
- Uveal Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PAC-1Drug
Pharmacokinetic (PK) and pharmacodynamic (PD) assay for PAC-1 will be performed during Days 1 and 21 of Cycle 1. PAC-1 will be given on Day 1 of Cycle 1, withheld on Day 2 and Day 3 of Cycle 1 then reinitiated on Day 4 of Cycle 1 to continue for 21 days of the 28-day cycle. For each successive cycle, PAC-1 therapy will be initiated on Day 1 and continue for 21 days of the 28-day cycle.
EntrectinibDrug
Pharmacokinetic and pharmacodynamic assay for entrectinib will be performed during Days 3 and 21 of Cycle 1. Entrectinib therapy will be withheld on Day 1 and Day 2 of Cycle 1, initiated on Day 3 of Cycle 1 and continue for the remainder of the 28 day cycle. For each successive cycle, entrectinib will be intiated on Day 1 and continue for 28 days of the 28-day cycle.
| Study group | Role | What they receive |
|---|---|---|
| Study Treatment Arm | Experimental | Phase 1b will determine the MTD of PAC-1 in combination with entrectinib. Study treatment will include: PAC-1 will be taken orally on Days 1-21 and Entrectinib will be taken orally on Days 1-28 of each 28-day cycle. Treatment will continue until disease progression (based on RECIST 1.1 criteria), unacceptable toxicity, subject withdrawal of informed consent, or subject death either from progression of disease, the therapy itself, or from other causes. Receives: Drug: PAC-1; Drug: Entrectinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: Determine Maximum Tolerated Dose (MTD)
The MTD of PAC-1 in combination with entrectinib is the highest tested dose of PAC-1 combined with entrectinib with DLT rate of less than 33% in first cycle of therapy (i.e., ≤1 out of 6 subjects with DLT)
Measured: 28 days
Phase 2: Progression Free Survival at 3 Months
PFS is defined as proportion of alive subjects with metastatic uveal melanoma at 3 months from treatment initiation with PAC-1 in combination with entrectinib without evidence of radiological disease progression by RECIST 1.1.
Measured: Time of treatment start until the criteria for disease progression.
Secondary outcomes (4)
Assess Adverse Events
The frequency and severity of all treatment related grade 1 and 2 adverse events are reported by CTCAEv5 term and grade.
Measured: AEs will be recorded from time of signed informed consent until 90 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 10 months.
Phase 2: Overall Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD.
ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.
Measured: Start of treatment until disease progression/recurrence
Phase 2: Duration of Response (DoR)
DoR is defined as the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented
Measured: Time from complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease.
Overall Survival (OS)
OS is defined as the time from treatment initiation with PAC-1 in combination with entrectinib until death as a result of any cause
Measured: up to a maximum of 15 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2020
- Study start11 Jan 2021
- Primary completion22 Mar 2022
- Study completion24 Jun 2022
Why it stopped: This study required dose reductions to the lower dose level (Dose level -1). But this dose level (Dose level -1) was not further explored because of lack of funding.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Uveal MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Arkadiusz Z. Dudek, MD
- Sponsor type
- University, hospital or other
- Collaborators
- HealthPartners Institute Regions Cancer Care Center, Vanquish Oncology, Inc., Genentech, Inc., Midwest Melanoma Partnership
- Responsible party
- Sponsor-investigator, Arkadiusz Z. Dudek, MD, Hoosier Cancer Research Network
- Investigators
- Arkadiusz Dudek, MD, PhD, Principal investigator, Health Partners Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04589832
- Sponsor's protocol ID
- MEL18-372
- Status last verified
- Nov 2023
- First submitted
- 9 Oct 2020
- Last updated
- 22 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Boudreau MW, Tonogai EJ, Schane CP, Xi MX, Fischer JH, Vijayakumar J, Ji Y, Tarasow TM, Fan TM, Hergenrother PJ, Dudek AZ. The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma. Melanoma Res. 2023 Dec 1;33(6):514-524. doi: 10.1097/CMR.0000000000000927. Epub 2023 Sep 22.
PubMed 37738028
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1B/2 Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma
- ClinicalTrials.gov ID
- NCT04589832
- Acronym / sponsor ID
- MEL18-372
- Conditions
- Uveal Melanoma
- Keywords
- uveal melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: This study required dose reductions to the lower dose level (Dose level -1). But this dose level (Dose level -1) was not further explored because of lack of funding.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Arkadiusz Z. Dudek, MDUniversity, hospital or other
- Collaborators
- HealthPartners Institute Regions Cancer Care Center, Vanquish Oncology, Inc., Genentech, Inc., Midwest Melanoma Partnership
- Study start
- 11 Jan 2021 (actual)
- Primary completion
- 22 Mar 2022 (actual)
- Study completion
- 24 Jun 2022 (actual)
- First posted
- 19 Oct 2020 (actual)
- Results
- Posted 22 Nov 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after every 2 cycles. Treatment will continue until disease progression based on RECIST criteria or intolerable toxicity.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Study Treatment Arm | Experimental | Drug: PAC-1, Drug: EntrectinibPhase 1b will determine the MTD of PAC-1 in combination with entrectinib. Study treatment will include: PAC-1 will be taken orally on Days 1-21 and Entrectinib will be taken orally on Days 1-28 of each 28-day cycle. Treatment will continue until disease progression (based on RECIST 1.1 criteria), unacceptable toxicity, subject withdrawal of informed consent, or subject death either from progression of disease, the therapy itself, or from other causes. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be willing and able to provide written informed consent for this trial.
- Age ≥ 18 years at the time of consent.
- Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC manual edition 8.
- One or more lesions that could be accurately measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 1).
Key exclusion criteria (20 listed)
- Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).
- Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
- Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. For patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg), the patient is only eligible if they are negative for HBV DNA.
- Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. NOTE: Radiation-induced lung disorders are not included in this exclusion criterion.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PAC-1Pharmacokinetic (PK) and pharmacodynamic (PD) assay for PAC-1 will be performed during Days 1 and 21 of Cycle 1. PAC-1 will be given on Day 1 of Cycle 1, withheld on Day 2 and Day 3 of Cycle 1 then reinitiated on Day 4 of Cycle 1 to continue for 21 days of the 28-day cycle. For each successive cycle, PAC-1 therapy will be initiated on Day 1 and continue for 21 days of the 28-day cycle. | Drug | Study Treatment Arm |
| EntrectinibPharmacokinetic and pharmacodynamic assay for entrectinib will be performed during Days 3 and 21 of Cycle 1. Entrectinib therapy will be withheld on Day 1 and Day 2 of Cycle 1, initiated on Day 3 of Cycle 1 and continue for the remainder of the 28 day cycle. For each successive cycle, entrectinib will be intiated on Day 1 and continue for 28 days of the 28-day cycle. | Drug | Study Treatment Arm |
Primary outcome
Phase 1b: Determine Maximum Tolerated Dose (MTD)
Time frame: 28 days
The MTD of PAC-1 in combination with entrectinib is the highest tested dose of PAC-1 combined with entrectinib with DLT rate of less than 33% in first cycle of therapy (i.e., ≤1 out of 6 subjects with DLT)
Phase 2: Progression Free Survival at 3 Months
Time frame: Time of treatment start until the criteria for disease progression.
PFS is defined as proportion of alive subjects with metastatic uveal melanoma at 3 months from treatment initiation with PAC-1 in combination with entrectinib without evidence of radiological disease progression by RECIST 1.1.
4 secondary outcomes
Assess Adverse Events
Time frame: AEs will be recorded from time of signed informed consent until 90 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 10 months.
Phase 2: Overall Response Rate (ORR)
Time frame: Start of treatment until disease progression/recurrence
Phase 2: Duration of Response (DoR)
Time frame: Time from complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease.
Overall Survival (OS)
Time frame: up to a maximum of 15 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37738028Boudreau MW, Tonogai EJ, Schane CP, Xi MX, Fischer JH, Vijayakumar J, Ji Y, Tarasow TM, Fan TM, Hergenrother PJ, Dudek AZ. The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma. Melanoma Res. 2023 Dec 1;33(6):514-524. doi: 10.1097/CMR.0000000000000927. Epub 2023 Sep 22.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arkadiusz Dudek, MD, PhD principal investigator
Health Partners Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PAC-1 and Entrectinib in people with Uveal Melanoma, run by Arkadiusz Z. Dudek, MD at 1 site in United States.
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 25 inclusion and 20 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: stopped early, as of the sponsor's last update on 22 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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 22 Nov 2023). 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?
Phase 1b: Determine Maximum Tolerated Dose (MTD) (time frame: 28 days). The study lists 2 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 NCT04589832, which also lists 1 linked publication.
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 22 Nov 2023.