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

NCT02702492 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: KCP-9274-901
• Study Type: interventional
• Target: 60
• Locations: 2 countries
• Sites: 8

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).

Conditions

Solid Tumors; NHL

Keywords

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

Outcome Measures

Primary Outcomes (9)

• Maximum Tolerated Dose (MTD) for KPT-9274

  The MTD was defined as the highest dose at which less than or equal to (\<=) 1 participant experienced a dose limiting toxicity (DLT) in Cycle 1. A DLT was defined as an adverse event (AE) or abnormal laboratory value occurring within the first 28 days of treatment of KPT-9274, excluding those clearly caused by underlying disease, disease progression, or external factors.

  From start of study drug administration up to 44 weeks

• Number of Dose Limiting Toxicities (DLT) Experienced by Participants

  A DLT was defined as an AE or abnormal laboratory value occurring within the first 28 days of KPT-9274 treatment, excluding those clearly caused by underlying disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose limiting toxicities.

  At Cycle 1 only (28-day cycle)

• Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation

  The AE severity was graded on a scale from 1 to 4 using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03; any events not specifically listed in the scale were defined as: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening. An SAE was any untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. The AE leading to treatment discontinuation in the study.

  From start of study drug administration up to 49 weeks

• Percentage of Participants With Overall Response Rate (ORR)

  The ORR was defined as percentage of participants who had a response of partial response (PR) or complete response (CR). The PR was achieved when a participant had at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non target) must have reduction in the short axis to \<10 millimeter (mm).

  From date of randomization up to 44 weeks

• Percentage of Participants With Disease Control Rate (DCR)

  The DCR was defined as percentage of participants who have a response of CR, PR, and stable disease (SD) \>= 16 weeks, DCR = CR + PR+ SD. The PR was achieved when a participant had at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non-target) must have reduction in the short axis to \<10mm. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).

  From date of the first study treatment up to 44 weeks

• Progression-free Survival (PFS)

  The PFS was defined as the duration of time from date of the first study treatment until the first date that PD is objectively documented or death due to any cause. The PD is defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Appearance of one or more new lesions will also constitute PD.

  From the date of first study treatment until the first date of PD, or death due (up to 44 weeks)

• Overall Survival (OS)

  The OS was defined as the duration of time from date of the first study treatment until death from any cause.

  From date of the first study treatment until death (up to 44 weeks)

• Time to Progression (TTP)

  The TTP was defined as the duration of time from date of the first study treatment until the first date that PD was objectively documented or death due to PD.

  From date of the first study treatment until the first date of PD or death (up to 44 weeks)

• Duration of Response (DOR)

  The DOR was defined as the duration of time from the first meeting CR or PR measurement criteria (whichever occurs first) until the first date diseases progression.

  Up to 44 weeks

Secondary Outcomes (5)

• Maximum Plasma Concentration (Cmax) in Participants Who Received KPT-9274

  Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)

• Time-to-peak Plasma Concentration (Tmax) in Participants Who Received KPT-9274

  Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)

• Terminal Half-life (T1/2) in Participants Who Received KPT-9274

  Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)

• Volume of Distribution (Vd/F) in Participants Who Received KPT-9274

  Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)

• Apparent Plasma Clearance (CL/F) in Participants Who Received KPT-9274

  Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)

Study Arms (13)

Part A: KPT-9274 10mg

EXPERIMENTAL

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

Drug: KPT-9274

Part A: KPT-9274 20mg

EXPERIMENTAL

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

Drug: KPT-9274

Part A: KPT-9274 30mg

EXPERIMENTAL

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

Drug: KPT-9274

Part A: KPT-9274 40mg

EXPERIMENTAL

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

Drug: KPT-9274

Part A: KPT-9274 40mg BIW

EXPERIMENTAL

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

Drug: KPT-9274

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

EXPERIMENTAL

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.

Drug: KPT-9274; Drug: Niacin ER

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

EXPERIMENTAL

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.

Drug: KPT-9274; Drug: Niacin ER

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

EXPERIMENTAL

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.

Drug: KPT-9274; Drug: Niacin ER

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

EXPERIMENTAL

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.

Drug: KPT-9274; Drug: Niacin ER

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

EXPERIMENTAL

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.

Drug: KPT-9274; Drug: Niacin ER

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

EXPERIMENTAL

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).

Drug: KPT-9274; Drug: Nivolumab

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

EXPERIMENTAL

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).

Drug: KPT-9274; Drug: Nivolumab

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

EXPERIMENTAL

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).

Drug: KPT-9274; Drug: Nivolumab

Interventions

KPT-9274 DRUG

Part A: KPT-9274 10mg; Part A: KPT-9274 20mg; Part A: KPT-9274 30mg; Part A: KPT-9274 40mg; Part A: KPT-9274 40mg BIW; Part B: KPT-9274 100mg + Niacin 500mg; Part B: KPT-9274 30mg + Niacin 500mg; Part B: KPT-9274 40mg + Niacin 500mg; Part B: KPT-9274 60mg + Niacin 500mg; Part B: KPT-9274 80mg + Niacin 500mg; Part C: KPT-9274 20mg + Nivolumab 480mg; Part C: KPT-9274 30mg + Nivolumab 480mg; Part C: KPT-9274 40mg + Nivolumab 480mg

Niacin ER DRUG

Part B: KPT-9274 100mg + Niacin 500mg; Part B: KPT-9274 30mg + Niacin 500mg; Part B: KPT-9274 40mg + Niacin 500mg; Part B: KPT-9274 60mg + Niacin 500mg; Part B: KPT-9274 80mg + Niacin 500mg

Nivolumab DRUG

Also known as: Opdivo®

Part C: KPT-9274 20mg + Nivolumab 480mg; Part C: KPT-9274 30mg + Nivolumab 480mg; Part C: KPT-9274 40mg + Nivolumab 480mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• ≤ 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.

Sponsors & Collaborators

• Karyopharm Therapeutics Inc: lead

Study Sites (8)

UCLA Health

Los Angeles, California, 90024, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Georgetown University, Lombardi Comprehensive Cancer Center

Washington D.C., District of Columbia, 20007, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

NYU-Laura & Isaac Perlmutter Cancer Center

New York, New York, 100016, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (3)

• Han W, Yang Y, Yu F, Li Q, Liu A, Xu W, Li J, Xue X. Design, synthesis and anticancer activity evaluation of 4-(3-1H-indazolyl)amino quinazoline derivatives as PAK4 inhibitors. Bioorg Med Chem. 2023 Nov 15;95:117501. doi: 10.1016/j.bmc.2023.117501. Epub 2023 Oct 13.

  PMID: 37864885 DERIVED

• 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.

  PMID: 34253597 DERIVED

• 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.

  PMID: 28062705 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

KPT-9274; Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

Study was terminated prematurely due to a lack of efficacy during primary analysis and therefore, efficacy, PK and PDn assessments were not determined.

Results Point of Contact

• Title: Karyopharm Medical Information
• Organization: Karyopharm Therapeutics Inc

clinicaltrials@karyopharm.com

(888) 209-9326

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2016
• First Posted: March 8, 2016
• Study Start: June 8, 2016
• Primary Completion: January 26, 2021
• Study Completion: January 26, 2021
• Last Updated: November 25, 2024
• Results First Posted: November 25, 2024

Record last verified: 2024-10

Locations

US (7); CA (1)