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

Karyopharm Therapeutics

Status and phase: Terminated; Phase 1

Conditions: NHL; Solid Tumors

Treatments: Drug: KPT-9274; Drug: Nivolumab; Drug: Niacin ER

Study type: Interventional

Funder types: Industry

Identifiers

NCT02702492

KCP-9274-901

Details and patient eligibility

About

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).

Full 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.

Enrollment: 60 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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60 participants in 13 patient groups

Part A: KPT-9274 10mg

Experimental group

Description:

Participants received a 10 milligrams (mg) of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.

Treatment:

Drug: KPT-9274

Part A: KPT-9274 20mg

Experimental group

Description:

Participants received a 20mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.

Treatment:

Drug: KPT-9274

Part A: KPT-9274 30mg

Experimental group

Description:

Participants received a 30mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.

Treatment:

Drug: KPT-9274

Part A: KPT-9274 40mg

Experimental group

Description:

Participants received a 40mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.

Treatment:

Drug: KPT-9274

Part A: KPT-9274 40mg BIW

Experimental group

Description:

Participants received KPT-9274 40mg of oral tablet biweekly (BIW) during each 28-day cycle.

Treatment:

Drug: KPT-9274

Part B: KPT-9274 30mg + Niacin 500mg

Experimental group

Description:

Participants received KPT-9274 30mg of oral tablet along with a starting dose of 500mg niacin extended release (ER) orally three times a week every other day during each 28-day cycle.

Treatment:

Drug: Niacin ER

Drug: KPT-9274

Part B: KPT-9274 40mg + Niacin 500mg

Experimental group

Description:

Participants received KPT-9274 40mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.

Treatment:

Drug: Niacin ER

Drug: KPT-9274

Part B: KPT-9274 60mg + Niacin 500mg

Experimental group

Description:

Participants received KPT-9274 60mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.

Treatment:

Drug: Niacin ER

Drug: KPT-9274

Part B: KPT-9274 80mg + Niacin 500mg

Experimental group

Description:

Participants received KPT-9274 80mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.

Treatment:

Drug: Niacin ER

Drug: KPT-9274

Part B: KPT-9274 100mg + Niacin 500mg

Experimental group

Description:

Participants received KPT-9274 100mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.

Treatment:

Drug: Niacin ER

Drug: KPT-9274

Part C: KPT-9274 20mg + Nivolumab 480mg

Experimental group

Description:

Participants received KPT-9274 20mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).

Treatment:

Drug: Nivolumab

Drug: KPT-9274

Part C: KPT-9274 30mg + Nivolumab 480mg

Experimental group

Description:

Participants received KPT-9274 30mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).

Treatment:

Drug: Nivolumab

Drug: KPT-9274

Part C: KPT-9274 40mg + Nivolumab 480mg

Experimental group

Description:

Participants received KPT-9274 40mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).

Treatment:

Drug: Nivolumab

Drug: KPT-9274