Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma

NCT04589832 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: MEL18-372
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief 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. Treatment will continue until disease progression based on RECIST criteria or intolerable toxicity.

Conditions

Uveal Melanoma

Keywords

uveal melanoma

Outcome Measures

Primary Outcomes (2)

• 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)

  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.

  Time of treatment start until the criteria for disease progression.

Secondary Outcomes (4)

• Assess Adverse Events

  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)

  Start of treatment until disease progression/recurrence

• Phase 2: Duration of Response (DoR)

  Time from complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease.

• Overall Survival (OS)

  up to a maximum of 15 months

Study Arms (1)

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.

Drug: PAC-1; Drug: Entrectinib

Interventions

PAC-1 DRUG

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.

Study Treatment Arm

Entrectinib DRUG

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 Treatment Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• Arkadiusz Z. Dudek, MD: lead
• HealthPartners Institute Regions Cancer Care Center: collaborator
• Vanquish Oncology, Inc.: collaborator
• Genentech, Inc.: collaborator
• Midwest Melanoma Partnership: collaborator

Study Sites (1)

HealthPartners Institute Regions Cancer Care Center

Minneapolis, Minnesota, 55440, United States

Location

Related Publications (1)

• 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.

  PMID: 37738028 DERIVED

MeSH Terms

Conditions

Uveal Melanoma

Interventions

entrectinib

Condition Hierarchy (Ancestors)

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Uveal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases

Results Point of Contact

• Title: Fauzia Sharmin
• Organization: Hoosier Cancer Research Network

fsharmin@hoosiercancer.org

(317) 921-2050

Study Officials

• Arkadiusz Dudek, MD, PhD

  Health Partners Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: October 9, 2020
• First Posted: October 19, 2020
• Study Start: January 11, 2021
• Primary Completion: March 22, 2022
• Study Completion: June 24, 2022
• Last Updated: November 22, 2023
• Results First Posted: November 22, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)