Clinical Trials /

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

NCT04589832

Description:

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.

Related Conditions:
  • Uveal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma
  • Official Title: Phase 1B/2 Study of PAC-1 and Entrectinib for Patients With Metastatic Uveal Melanoma

Clinical Trial IDs

  • ORG STUDY ID: MEL18-372
  • NCT ID: NCT04589832

Conditions

  • Uveal Melanoma

Interventions

DrugSynonymsArms
PAC-1Study Treatment Arm
EntrectinibStudy Treatment Arm

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Study Treatment ArmExperimentalPhase 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.
  • PAC-1
  • Entrectinib

Eligibility Criteria

        Inclusion Criteria

          1. 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.

          2. Age ≥ 18 years at the time of consent.

          3. Histologically or cytologically confirmed metastatic uveal melanoma. Staging per AJCC
             manual edition 8.

          4. One or more lesions that could be accurately measured using Response Evaluation
             Criteria in Solid Tumors (RECIST) 1.1.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 1).

          6. 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

               -  Alkaline Phosphatase ≤ 2.5 × ULN

               -  Partial Thromboplastin Time (PTT) < 1.5 × ULN

          7. 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.

          8. Prior therapy is allowed but must have been completed 21 days prior to initiation of
             protocol therapy and all toxicities must be < Grade 2.

          9. Palliative radiation must have been completed 2 weeks prior to the initiation of study
             therapy.

         10. 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).

         11. Women of childbearing potential (WOCBP) must agree to use contraception as outlined in
             Section 5.8 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 from the time
             of informed consent, during study treatment and for 3 months after the last dose of
             study drug(s) 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.

         12. Male patients who are sexually active with WOCBP must agree to use contraception as
             outlined in Section 5.8 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 from the time of initiation of study treatment, during study
             treatment and for 3 months after the last dose of study drug(s) is an acceptable form
             of contraception.

         13. The participant is capable of understanding and complying with the protocol and has
             signed informed consent document.

        Exclusion Criteria

          1. Peripheral sensory neuropathy Grade ≥ 2 (per CTCAE v5.0).

          2. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short
             gut syndrome) or other malabsorption syndromes that would reasonably impact drug
             absorption.

          3. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          4. 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.

          5. 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.

          6. 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.

          7. History of uncontrolled seizures.

          8. History of ataxia.

          9. Allergies and adverse drug reaction: History of allergy to study drug components.

         10. 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.

         11. History of recent (within the past 3 months) symptomatic congestive heart failure or
             ejection fraction ≤ 50% observed during screening for the study.

         12. History of prolonged QTc interval (e.g., repeated demonstration of a QTc interval >
             450 milliseconds from ECGs performed at least 24 hours apart).

         13. History of additional risk factors for torsades de pointes (e.g., family history of
             long QT syndrome).

         14. 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.

         15. Active infection requiring intravenous systemic treatment.

         16. Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration.

         17. Known uncontrolled, symptomatic brain metastasis or cranial epidural disease.

         18. Known additional malignancies which require systemic treatment.

         19. Inability to swallow intact tablets.

         20. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b: Determine maximum tolerated dose (MTD) of PAC-1
Time Frame:28 days
Safety Issue:
Description: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)

Secondary Outcome Measures

Measure:Incidence and severity of adverse events
Time Frame:12 months
Safety Issue:
Description:Evaluate the safety of entrectinib and PAC-1 combination, assessed by the incidence and severity of drug-related adverse events (AE), in subjects with metastatic uveal melanoma. CTCAE v5 for grading adverse events
Measure:Overall Response Rate (ORR)
Time Frame:12 months
Safety Issue:
Description:Number of subjects with complete response and partial response determined as per RECIST 1.1
Measure:Duration of Response (DoR)
Time Frame:12 months
Safety Issue:
Description: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
Measure:Overall Survival (OS)
Time Frame:12 months
Safety Issue:
Description:OS is defined as the time from treatment initiation with PAC-1 in combination with entrectinib until death as a result of any cause

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Arkadiusz Z. Dudek, MD

Trial Keywords

  • uveal melanoma

Last Updated

January 13, 2021