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

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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

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.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Phase 1b: Determine maximum tolerated dose (MTD) of PAC-1

Secondary Outcome

 Incidence and severity of adverse events

Condition

Uveal Melanoma

Intervention

PAC-1

Study Arms / Comparison Groups

 Study Treatment Arm
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

38

Start Date

January 11, 2021

Completion Date

June 2022

Primary Completion Date

June 2021

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 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.

         12. 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

         13. 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.

         14. 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Arkadiusz Dudek, MD, PhD, 657-482-8200, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04589832

Organization ID

MEL18-372


Responsible Party

Sponsor-Investigator

Study Sponsor

Arkadiusz Z. Dudek, MD

Collaborators

 HealthPartners Regions Cancer Care and Frauenshuh Cancer Care Centers

Study Sponsor

Arkadiusz Dudek, MD, PhD, Principal Investigator, Health Partners Institute


Verification Date

February 2021