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

Study Overview
=================
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.

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.

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

Conditions
-----------------
Solid Tumors, NHL

Intervention / Treatment
-----------------
* Drug: KPT-9274
* Drug: Niacin ER
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants must meet all of the following inclusion criteria to be eligible to enroll in the Part C of this study. 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. ECOG performance status of ≤ 2. Life expectancy of ≥ 3 months. 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). 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. 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. ≤ 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. 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. 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. Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within one week prior to C1D1. Prophylactic antibiotics, antivirals or antifungals are permitted. Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-9274. Active peptic ulcer disease or other active gastrointestinal bleeds. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KPT-9274<br>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<br> <br> |
| Experimental: KPT-9274 & Niacin Extended Release (ER)<br>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<br> <br> Drug: Niacin ER<br> <br> |
| Experimental: KPT-9274 + Nivolumab<br>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<br> <br> Drug: Nivolumab<br> <br> * Other names: Opdivo®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) for KPT-9274 administered alone and with co-administration of niacin ER (extended release) (vitamin B3/nicotinic acid) | 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. | Approximately 4 weeks | 
| Maximum tolerated dose (MTD) for KPT-9274 co-administered with nivolumab | 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. | Approximately 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PAK4, KPT-9274, Karyopharm, NHL, Solid Tumors, NAMPT, Melanoma