Study of the Safety, Tolerability and Efficacy of KPT-8602 in Participants With Relapsed/Refractory Cancer Indications

NCT02649790 | Completed Phase 1 FDA Drug

• 1 other identifier: KCP-8602-801
• Study Type: interventional
• Target: 277
• Locations: 5 countries
• Sites: 46

Brief Summary

This is a first-in-human, multi-center, open-label clinical study with separate dose escalation (Phase 1) and expansion (Phase 2) stages to assess preliminary safety, tolerability, and efficacy of the second generation oral XPO1 inhibitor KPT-8602 in participants with relapsed/refractory multiple myeloma (MM), metastatic colorectal cancer (mCRC), metastatic castration resistant prostate cancer (mCRPC), higher risk myelodysplastic syndrome (HRMDS), acute myeloid leukemia (AML) and newly diagnosed intermediate/high-risk MDS. Dose escalation and dose expansion may be included for all parts of the study as determined by ongoing study results.

Conditions

Relapsed/Refractory Multiple Myeloma (RRMM); Metastatic Colorectal Cancer (mCRC); Metastatic Castration-Resistant Prostate Cancer (mCRPC); Higher-Risk Myelodysplastic Syndrome (HR-MDS); Acute Myeloid Leukemia (AML); Newly Diagnosed Intermediate/High-Risk MDS

Keywords

Multiple Myeloma; Karyopharm; KPT-8602; MM; Phase 1; Relapsed/ Refractory Multiple Myeloma; Myelodysplastic Syndrome; MDS; Metastatic Castration-Resistant Prostate Cancer; mCRPC; CRC; Metastatic Colorectal Cancer; AML

Outcome Measures

Primary Outcomes (12)

• Part A1, A2, B, C, D, E, F: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

  Approximately 4 weeks

• Part A1, A2, B, C, D, E, F: Overall Response Rate (ORR)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Duration of Response (DOR)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Progression-free Survival (PFS)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Overall Survival (OS)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Clinical Benefit Rate (CBR)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Duration of Clinical Benefit Rate (CBR)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Disease Control Rate (DCR)

  Approximately 8 years

• Part A1, A2, B, C, D, E, F: Duration of DCR

  Approximately 8 years

• Part F Phase 2: ORR

  Approximately 8 years

• Part G: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

  Approximately 8 years

• Part H: 2- Year Progression-free Survival (PFS)

  Approximately Up to 2 years

Secondary Outcomes (20)

• Part A1, A2, B, C, D, E, F, H: Area Under the Plasma Concentration Time Curve from Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Eltanexor

  Pre-dose 2 hours post-dose Cycle 1 Day 1 and 15; Pre-dose 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 21 and 26; 24 hours post-dose Cycle 1 Day 2, 22, and 27; 48 hours post-dose Cycle 1 Day 23 and 28 and up to approximately 8 years

• Part A1, A2, B, C, D, E, F, H: Maximum Observed Plasma Concentration (Cmax) of Eltanexor

  Pre-dose 2 hours post-dose Cycle 1 Day 1 and 15; Pre-dose 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 21 and 26; 24 hours post-dose Cycle 1 Day 2, 22, and 27; 48 hours post-dose Cycle 1 Day 23 and 28 and up to approximately 8 years

• Part A1, A2, B, C, D, E, F, H: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Eltanexor

  Pre-dose 2 hours post-dose Cycle 1 Day 1 and 15; Pre-dose 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 21 and 26; 24 hours post-dose Cycle 1 Day 2, 22, and 27; 48 hours post-dose Cycle 1 Day 23 and 28 and up to approximately 8 years

• Part A1, A2, B, C, D, E, F, H: Apparent Terminal Half Life (t1/2) of Eltanexor

  Pre-dose 2 hours post-dose Cycle 1 Day 1 and 15; Pre-dose 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 21 and 26; 24 hours post-dose Cycle 1 Day 2, 22, and 27; 48 hours post-dose Cycle 1 Day 23 and 28 and up to approximately 8 years

• Part A1, A2, B, C, D, E, F, H: Apparent Total Body Clearance Eltanexor

  Pre-dose 2 hours post-dose Cycle 1 Day 1 and 15; Pre-dose 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 21 and 26; 24 hours post-dose Cycle 1 Day 2, 22, and 27; 48 hours post-dose Cycle 1 Day 23 and 28 and up to approximately 8 years

Study Arms (10)

Part A1: RRMM- KPT-8602 single agent; QoDx5/week

EXPERIMENTAL

Participants received KPT-8602 once daily for 5 days per week (QDx5/week) at escalated doses (completed).

Drug: KPT-8602

Part A2: RRMM- KPT-8602 single agent; QoDx3/week

EXPERIMENTAL

Participants received KPT-8602 once daily for 3 days per week (QoDx3/week). The starting dose for Part A2 will be informed by Part A1 (completed).

Drug: KPT-8602

Part B: RRMM- KPT-8602 with low-dose dexamethasone; QDx5/week

EXPERIMENTAL

Participants received KPT-8602 for 5 consecutive days (QDx5/week) in combination with low dose dexamethasone (20 milligram \[mg\] on Days 1, 3, 8, 10, 15, 17, 22, and 24 of each 28-day cycle) (completed).

Drug: KPT-8602; Drug: Dexamethasone

Part C: CRC- KPT-8602 single agent

EXPERIMENTAL

Participants were treated with KPT-8602 at a dose and schedule that has been cleared in Part A (completed).

Drug: KPT-8602

Part D: mCRPC- KPT-8602 single agent

EXPERIMENTAL

Participants were treated with KPT-8602 at a dose and schedule that has been cleared in Part A (completed).

Drug: KPT-8602

Part E: mCRPC- KPT-8602 with abiraterone and corticosteroids

EXPERIMENTAL

Participants were treated with KPT-8602 at a dose and schedule that had been cleared in Part A in combination with abiraterone and corticosteroids. Participants continued to receive the dose and schedule of abiraterone and corticosteroids that they were receiving at the time of enrollment (completed).

Drug: KPT-8602

Part F: High-risk Myelodysplastic Syndrome (MDS)- KPT-8602 single agent

EXPERIMENTAL

Participants were treated with KPT-8602 at a dose and schedule that had been cleared in Part A. In select cases (for example, participants achieving stable disease \[SD\], hematological improvement \[HI\], partial response \[PR\] and tolerating treatment, etc.), the dose may be escalated 1 level based on safety and efficacy considerations (completed).

Drug: KPT-8602

Part F Phase 2: RR High-risk MDS- KPT-8602 single agent

EXPERIMENTAL

Participants will be enrolled at recommended Phase 2 doses (RP2D) of 10 mg daily on Days 1 to 5 of each week, in a dose expansion, based upon the results from the Phase 1 portion of Part F.

Drug: KPT-8602

Part G: Newly Diagnosed Intermediate/High-Risk MDS -KPT-8602 with ASTX727

EXPERIMENTAL

Participants will receive KPT-8602 once daily at escalated doses. The starting dose for KPT-8602 is 5 mg orally once daily from Day 8 to Day 28 (Weeks 2 to 4) on a 28-day cycle in combination with ASTX727.

Drug: KPT-8602; Drug: ASTX727

Part H: AML Maintenance Therapy- KPT-8602 single agent

EXPERIMENTAL

Participants with high-risk acute myeloid leukemia (AML) prior to transplant will be enrolled to receive maintenance therapy with KPT-8602 post-allogeneic stem cell transplantation. The dose for KPT-8602 will be 10 mg (RP2D from Part F) oral, to be administered once daily from Day 1 to Day 21 (Weeks 1 to 3) on a 28-day cycle.

Drug: KPT-8602

Interventions

KPT-8602 DRUG

Participants will receive KPT-8602 oral tablets.

Also known as: Eltanexor

Part A1: RRMM- KPT-8602 single agent; QoDx5/week; Part A2: RRMM- KPT-8602 single agent; QoDx3/week; Part B: RRMM- KPT-8602 with low-dose dexamethasone; QDx5/week; Part C: CRC- KPT-8602 single agent; Part D: mCRPC- KPT-8602 single agent; Part E: mCRPC- KPT-8602 with abiraterone and corticosteroids; Part F Phase 2: RR High-risk MDS- KPT-8602 single agent; Part F: High-risk Myelodysplastic Syndrome (MDS)- KPT-8602 single agent; Part G: Newly Diagnosed Intermediate/High-Risk MDS -KPT-8602 with ASTX727; Part H: AML Maintenance Therapy- KPT-8602 single agent

ASTX727 DRUG

ASTX727 is a combination drug of 35 mg decitabine and 100 mg cedazuridine.

Part G: Newly Diagnosed Intermediate/High-Risk MDS -KPT-8602 with ASTX727

Dexamethasone DRUG

Participants will receive dexamethasone oral tablets.

Part B: RRMM- KPT-8602 with low-dose dexamethasone; QDx5/week

Eligibility Criteria

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

You may qualify if:

• Written informed consent signed prior to any screening procedures and in accordance with federal, local, and institutional guidelines.
• Age ≥ 18 years.
• Adequate hepatic function:
• total bilirubin ≤ 2 times the upper limit of normal (ULN) (except participants with Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\] who must have a total bilirubin of ≤ 4 times ULN),
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (except participants with known liver involvement of their tumor who must have their AST and ALT ≤ 5.0 times ULN).
• Adequate renal function: estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockcroft and Gault (140-Age) × Mass (kg)/(72 × creatinine mg/dL); multiply by 0.85 if female.
• Contraception:
• Participants with RRMM, CRC, RR high-risk MDS (Part F Phase 2), and AML (Part H): Female participants of child-bearing potential must agree to use dual methods of contraception (including 1 highly effective and 1 effective method of contraception) and have a negative serum test at Screening, and male participants must use an effective barrier method of contraception if sexually active. For both male and female participants, effective methods of contraception must be used throughout the study and for 3 months following the last dose
• Participants with RR mCRPC: Participants must use an effective barrier method of contraception if sexually active. Effective methods of contraception must be used throughout the study and for 3 months following the last dose
• Participants with newly diagnosed intermediate/high-risk MDS (Part G): Female participants of child-bearing potential must agree to use dual methods of contraception (including 1 highly effective and 1 effective method of contraception) and have a negative serum pregnancy test at Screening, and male participants must use an effective barrier method of contraception if sexually active. For both male and female participants, effective methods of contraception must be used throughout the study and for 6 months following the last dose
• Relapsed/Refractory Multiple Myeloma (Parts A1, A2, and B - Completed):
• Symptomatic, histologically confirmed MM and evidence of disease progression, based on IMWG guidelines.
• Participants must have measurable disease as defined by at least 1 of the following:
• Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or for immunoglobulin (Ig) A myeloma, by quantitative IgA. If SPEP is felt to be unreliable for routine M-protein measurement (e.g., for participants with IgA MM), then quantitative Ig levels by nephelometry; or
• Urinary M-protein excretion at least 200 mg/24 hours; or

You may not qualify if:

• Participants in All Parts of the Study:
• Female participants who are pregnant or lactating.
• Major surgery within 4 weeks before C1D1.
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• Unstable angina or acute myocardial infarction ≤ 3 months prior to C1D1
• Clinically significant heart disease (e.g., symptomatic congestive heart failure \[e.g., \> NYHA Class 2\]; uncontrolled arrhythmia, or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen)
• Uncontrolled active severe systemic infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1.
• Participants with known symptomatic brain metastasis are not suitable for enrollment. Participants with asymptomatic, stable, treated brain metastases are eligible for study entry
• Participants with a known history of human immunodeficiency virus (HIV); HIV testing is not required as part of this study
• Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen)
• Prior malignancies:
• Participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (i.e., cervix) may enroll irrespective of the time of diagnosis
• Participants with relapsed/refractory MM, CRC, and mCRPC only: Prior malignancies which may interfere with the interpretation of the study. Cancer treated with curative intent \< 5 years previously will not be allowed unless approved by the Sponsor. Cancer treated with curative intent \> 5 years previously and without evidence of recurrence will be allowed.
• Participants with gastrointestinal tract disease (or uncontrolled vomiting or diarrhea) that could interfere with the absorption of eltanexor (or ASTX727 in Part G).
• Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give consent.

Sponsors & Collaborators

• Karyopharm Therapeutics Inc: lead

Study Sites (46)

David Geffen School of Medicine at UCLA

Los Angeles, California, 90095, United States

Location

Oncology Institute of Hope and Innovation

Pasadena, California, 91105, United States

Location

Rocky Mountain Regional VA Medical Center

Aurora, Colorado, 80045, United States

Location

Sarah Cannon Cancer Center - (Colorado Blood Cancer Institute)

Denver, Colorado, 80218, United States

Location

(USO) Rocky Mountain Cancer Centers

Littleton, Colorado, 80120-4413, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Cancer and Hematology Centers of Western Michigan

Grand Rapids, Michigan, 49503, United States

Location

Sarah Cannon Cancer Center (HCA Midwest KC)

Kansas City, Missouri, 64132, United States

Location

Callahan Cancer Center

North Platte, Nebraska, 69101, United States

Location

John Theurer Cancer Center at Hackensack UMC

Hackensack, New Jersey, 07601, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

(USO) Oncology Hematology Care

Cincinnati, Ohio, 45236, United States

Location

Ohio State University, The James Cancer Hospital and Solove Research Institute

Columbus, Ohio, 43210, United States

Location

University of Pennsylvania Abramson Cancer Center Clinical Research Unit

Philadelphia, Pennsylvania, 19104, United States

Location

Baptist Cancer Center

Memphis, Tennessee, 38120, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

(USO) Texas Oncology Austin - Midtown

Austin, Texas, 78705, United States

Location

(USO) Texas Oncology (Dallas)

Dallas, Texas, 75246, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

(USO) Texas Oncology (Tyler)

Tyler, Texas, 75702, United States

Location

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

(USO) Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

Location

University of Washington

Seattle, Washington, 98109, United States

Location

(USO) Compass oncology

Vancouver, Washington, 98684, United States

Location

McMaster - Juravinski Cancer Centre

Hamilton, Ontario, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 2M9, Canada

Location

Princess Margaret Cancer Research

Toronto, Ontario, Canada

Location

MUHC GLEN Site Cedars - Cancer Centre

Montreal, Quebec, Canada

Location

China, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430022, China

Location

Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences

Tianjin, Tianjin Municipality, 300041, China

Location

CHU Nantes

Nantes, 44000, France

Location

Hôpital Cochin APHP

Paris, 75014, France

Location

Hôpital Necker

Paris, 75015, France

Location

Hôpital St Louis

Paris, France

Location

CHU de Bordeaux

Pessac, 33604, France

Location

CHU de Tours

Tours, 37044, France

Location

CHRU de Nancy

Vandœuvre-lès-Nancy, 54500, France

Location

Clínica Universidad de Navarra

Barcelona, 08036, Spain

Location

Hospital San Pedro de Alcántara

Cáceres, Spain

Location

Clinical Universidad de Navarra (Madrid site)

Madrid, 28027, Spain

Location

Hospital 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Central Asturias

Oviedo, Spain

Location

Hospital Clínic of Barcelona

Pamplona, 31008, Spain

Location

Hospital La Fe

Valencia, Spain

Location

Related Publications (1)

• Lee S, Mohan S, Knupp J, Chamoun K, de Jonge A, Yang F, Baloglu E, Shah J, Kauffman MG, Shacham S, Bhatnagar B. Oral eltanexor treatment of patients with higher-risk myelodysplastic syndrome refractory to hypomethylating agents. J Hematol Oncol. 2022 Aug 3;15(1):103. doi: 10.1186/s13045-022-01319-y.

  PMID: 35922861 DERIVED

MeSH Terms

Conditions

Multiple Myeloma; Colorectal Neoplasms; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Eltanexor; decitabine and cedazuridine drug combination; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Leukemia, Myeloid; Leukemia; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Design

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

Study Record Dates

• First Submitted: January 6, 2016
• First Posted: January 7, 2016
• Study Start: January 1, 2016
• Primary Completion: August 31, 2024
• Study Completion: December 23, 2024
• Last Updated: March 19, 2025

Record last verified: 2025-03

Locations

ES (7); CA (4); CN (2); FR (7); US (26)