PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA) (PANAMA)

• ClinicalTrials.gov Identifier: NCT02702492
• Recruitment Status: Terminated
• First Posted: March 8, 2016
• Last Update Posted: January 19, 2023
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Study Description

Brief Summary:

This study will evaluate the safety, tolerability, and efficacy of oral KPT-9274 for the treatment of patients with advanced solid malignancies or non-Hodgkin's lymphoma (NHL). Currently enrolling melanoma patients in combination with nivolumab, only.

Condition or disease	Intervention/treatment	Phase
Solid Tumors; NHL	Drug: KPT-9274; Drug: Niacin ER; Drug: Nivolumab	Phase 1

Detailed Description:

This is a first-in-human, multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of KPT-9274, a dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies (including sarcoma, colon, lung, melanoma, etc.) or NHL for which all standard therapeutic options considered useful by the investigator have been exhausted.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Malignancies or Non-Hodgkin's Lymphoma
• Actual Study Start Date: June 2016
• Actual Primary Completion Date: February 1, 2021
• Actual Study Completion Date: June 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: KPT-9274; Part A: [CLOSED TO ENROLLMENT] Oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28 day cycle.	Drug: KPT-9274
Experimental: KPT-9274 & Niacin Extended Release (ER); Part B:[CLOSED TO ENROLLMENT] 500 mg niacin ER co-administered with each dose of oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28 day cycle.	Drug: KPT-9274; Drug: Niacin ER
Experimental: KPT-9274 + Nivolumab; Part C: Oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28 day cycle. Nivolumab 480 mg IV administered Day 1 during each 28 day cycle.	Drug: KPT-9274; Drug: Nivolumab; Other Name: Opdivo®

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose (MTD) for KPT-9274 administered alone and with co-administration of niacin ER (extended release) (vitamin B3/nicotinic acid) [ Time Frame: Approximately 4 weeks ]
   Parts A & B: MTD will be based on the assessment of dose limiting toxicities (DLTs) during the first cycle of therapy and will be defined as the highest dose at which ≤1 participant out of 6 (or 0 out of 3) experiences DLTs within Cycle 1.
2. Maximum tolerated dose (MTD) for KPT-9274 co-administered with nivolumab [ Time Frame: Approximately 4 weeks ]
   Part C: MTD will be based on the assessment of dose limiting toxicities (DLTs) during the first cycle of therapy and will be defined as the highest dose at which ≤ 1 participant out of 6 (or 0 out of 3) experiences DLTs within Cycle 1.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Participants must meet all of the following inclusion criteria to be eligible to enroll in the Part C of this study.

1. Should have unresectable advanced, recurrent or metastatic melanoma and must have objective and measurable melanoma by RECIST 1.1 after disease progression on a prior anti-PD-1 or anti-PD-L1 therapy.
2. ECOG performance status of ≤ 2.
3. Life expectancy of ≥ 3 months.

4. Adequate hepatic function:

   • Total bilirubin < 1.5 times the ULN (except participants with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3 times ULN),
   • AST and ALT ≤ 2.5 times ULN (except participants with known liver involvement of their advanced solid malignancy who must have an AST and ALT ≤ 5.0 times ULN).

5. Adequate renal function:

   • Estimated creatinine clearance of ≥ 60 mL/min, calculated using the formula of Cockroft and Gault (140-Age) Mass (kg)/(72 creatinine mg/dL); multiply by 0.85 if female.

6. Adequate hematopoietic function:

   • Total WBC count ≥ 1500/mm³, ANC ≥ 1000/mm³, Hb ≥ 10.0 g/dL, platelet count ≥ 100,000/mm³

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not eligible to enroll in this study.

1. ≤ 2 weeks since the last prior therapeutic regimen for melanoma. Palliative steroids for disease related symptoms < 7 days prior to C1D1, unless physiologic doses of steroids are used.
2. Have not recovered or stabilized (Gr 1 or to their baseline for non-hematologic toxicities, ≤ Gr 2 or to their baseline for hematologic toxicities) from toxicities related to their previous treatment except for alopecia.
3. Untreated CNS disease or leptomeningeal involvement are excluded. Participants without active brain or leptomeningeal metastases after prior treatment with local therapies are eligible provided that the treatment had been done ≥ 2 weeks prior to enrollment.
4. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within one week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are permitted.
5. Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-9274.
6. Active peptic ulcer disease or other active gastrointestinal bleeds.
7. Requiring treatment with corticosteroids at doses higher than substitute therapy (> 10 mg prednisone), are unstable with substitute hormonal therapy, or are deemed to be likely to re-occur by the treating physician when administered nivolumab.

Contacts and Locations

Locations

United States, California

UCLA Health

Los Angeles, California, United States, 90024

United States, Colorado

University of Colorado Cancer Center

Aurora, Colorado, United States, 80045

United States, District of Columbia

Georgetown University, Lombardi Comprehensive Cancer Center

Washington, District of Columbia, United States, 20007

United States, Minnesota

Mayo Clinic Rochester

Rochester, Minnesota, United States, 55905

United States, New York

NYU-Laura & Isaac Perlmutter Cancer Center

New York, New York, United States, 100016

United States, Tennessee

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States, 37232

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

Canada, Ontario

Princess Margaret Hospital

Toronto, Ontario, Canada, M5G 2M9

Sponsors and Collaborators

Karyopharm Therapeutics Inc

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mpilla GB, Uddin MH, Al-Hallak MN, Aboukameel A, Li Y, Kim SH, Beydoun R, Dyson G, Baloglu E, Senapedis WT, Landesman Y, Wagner KU, Viola NT, El-Rayes BF, Philip PA, Mohammad RM, Azmi AS. PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus. Mol Cancer Ther. 2021 Oct;20(10):1836-1845. doi: 10.1158/1535-7163.MCT-20-1105. Epub 2021 Jul 12.

Aboukameel A, Muqbil I, Senapedis W, Baloglu E, Landesman Y, Shacham S, Kauffman M, Philip PA, Mohammad RM, Azmi AS. Novel p21-Activated Kinase 4 (PAK4) Allosteric Modulators Overcome Drug Resistance and Stemness in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther. 2017 Jan;16(1):76-87. doi: 10.1158/1535-7163.MCT-16-0205. Epub 2016 Nov 15.

• Responsible Party: Karyopharm Therapeutics Inc
• ClinicalTrials.gov Identifier: NCT02702492
• Other Study ID Numbers: KCP-9274-901
• First Posted: March 8, 2016
• Last Update Posted: January 19, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Karyopharm Therapeutics Inc:

PAK4; KPT-9274; Karyopharm; NHL; Solid Tumors; NAMPT; Melanoma

Additional relevant MeSH terms:

Neoplasms; Niacin; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypolipidemic Agents; Antimetabolites; Lipid Regulating Agents; Vasodilator Agents; Vitamin B Complex; Vitamins; Micronutrients; Physiological Effects of Drugs