Clinical trial NCT02702492: PAK4 and NAMPT in Patients With Solid Malignancies or NHL (PANAMA)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors
NHL
Keywords: PAK4
KPT-9274
Karyopharm
NHL
Solid Tumors
NAMPT
Melanoma
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2016-03-08
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) for KPT-9274
timeFrame: From start of study drug administration up to 44 weeks
measure: Number of Dose Limiting Toxicities (DLT) Experienced by Participants
timeFrame: At Cycle 1 only (28-day cycle)
measure: Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation
timeFrame: From start of study drug administration up to 49 weeks
measure: Percentage of Participants With Overall Response Rate (ORR)
timeFrame: From date of randomization up to 44 weeks
measure: Percentage of Participants With Disease Control Rate (DCR)
timeFrame: From date of the first study treatment up to 44 weeks
measure: Progression-free Survival (PFS)
timeFrame: From the date of first study treatment until the first date of PD, or death due (up to 44 weeks)
measure: Overall Survival (OS)
timeFrame: From date of the first study treatment until death (up to 44 weeks)
measure: Time to Progression (TTP)
timeFrame: From date of the first study treatment until the first date of PD or death (up to 44 weeks)
measure: Duration of Response (DOR)
timeFrame: Up to 44 weeks
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) in Participants Who Received KPT-9274
timeFrame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
measure: Time-to-peak Plasma Concentration (Tmax) in Participants Who Received KPT-9274
timeFrame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
measure: Terminal Half-life (T1/2) in Participants Who Received KPT-9274
timeFrame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
measure: Volume of Distribution (Vd/F) in Participants Who Received KPT-9274
timeFrame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
measure: Apparent Plasma Clearance (CL/F) in Participants Who Received KPT-9274
timeFrame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Health
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Washington
country: United States
facility: Georgetown University, Lombardi Comprehensive Cancer Center
state: District of Columbia
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: NYU-Laura & Isaac Perlmutter Cancer Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
References:
citation: 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.
citation: 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.