Venetoclax and Selinexor in Treating Patients with Relapsed or Refractory High Risk Hematologic Malignancies

NCT03955783 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: VICC HEM 1755NCI-2019-02953
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 4

Brief Summary

This phase Ib trial studies the toxicity and dosing of venetoclax in combination with selinexor, and how well the combination works in treatment of patients with high risk hematologic malignancies such as diffuse large B-cell lymphoma and acute myeloid leukemia that has come back (recurrent) or does not respond to initial treatment (refractory). Venetoclax functions by inhibiting a protein in the body called bcl-2, which is involved in slowing down the normal process by which old cells in the body are cleared (called apoptosis). Selinexor functions by trapping "tumor suppressing proteins" within the cell and causing the cancer cells to die or stop growing. This study examines the effects, if any, of selinexor and venetoclax on high risk hematologic malignancies and on the body, including any side-effects.

Conditions

Diffuse Large B-cell Lymphoma; Acute Myeloid Leukemia; Non-Hodgkin's Lymphoma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (escalation)

  Up to 28 days

• Overall response rate (expansion)

  At 12 weeks

Secondary Outcomes (2)

• Progression free survival

  Up to 2 years

• Overall survival

  Up to 2 years

Study Arms (1)

Treatment (venetoclax, selinexor)

EXPERIMENTAL

Patients receive venetoclax PO QD on days 1-28. Patients with DLBCL receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Venetoclax naïve AML patients receive selinexor on days 8, 15, and 22 of cycle 1, followed by days 1, 8, 15, and 22 of subsequent cycles. Venetoclax refractory AML patients receive selinexor PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Venetoclax; Drug: Selinexor

Interventions

Venetoclax DRUG

Given by mouth

Treatment (venetoclax, selinexor)

Selinexor DRUG

Given by mouth

Treatment (venetoclax, selinexor)

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 in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
• Age ≥ 18 years
• Life expectancy \> 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically confirmed diagnosis of one of the following, in accordance with WHO diagnostic criteria:
• Escalation:
• Diffuse Large B-cell Lymphoma (DLBCL, including primary mediastinal large B cell lymphoma, T cell rich B cell lymphoma, and high-grade B cell lymphoma NOS). Patients with Burkitt's, lymphoblastic lymphoma, follicular lymphoma, and mantle cell lymphoma are not included. OR
• Acute Myeloid Leukemia (AML)
• Expansion:
• Diffuse Large B-cell Lymphoma and acute myeloid leukemia as above.
• VEN Refractory expansion cohort (Diffuse Large B-cell Lymphoma and acute myeloid leukemia only): Patients must have previously received and failed venetoclax therapy (either monotherapy or combination) during their treatment course (i.e., patients may receive non-VEN therapy immediately prior to enrollment on this study). Treatment failure is defined as evidence of disease progression after ≥ 1 cycle (four weeks) of full-intensity venetoclax-based therapy (i.e., 28 days exclusive of ramp-up. Patients that require dose reductions due to intolerance may be considered for this cohort after discussion with the sponsor.)
• Relapsed or refractory following ≥ 1 line(s) of prior therapy
• Patients that relapse ≥ 3 months after allogeneic hematopoietic cell transplantation (HCT) are eligible.
• Female patients of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment.
• For leukemia and DLBCL with known or suspected marrow involvement, patients must have at least 10-15 mL of bone marrow aspirate material obtained within 14 days of beginning treatment on this study. Patients with DLBCL must have 3-5 unstained slides, or tissue block, available for evaluation within 14 days of study enrollment in the expansion cohorts. DLBCL patients enrolled during the escalation phase must have blocks available for submission within 28 days of beginning treatment.

You may not qualify if:

• Patients who are pregnant or lactating
• Patients who received any systemic anticancer therapy including investigational agents or radiation ≤3 weeks (or ≤5 half-lives of the drug \[whichever is shorter\]) prior to C1D1. Hydroxyurea is permitted for up to 14 days in AML patients
• Inadequate recovery from toxicity attributed to prior anti-cancer therapy. With the exception of alopecia or fatigue, patients must have recovered to baseline or ≤ Grade 1 (NCI-CTCAE v4.03) residual toxicity prior to first dose of protocol-indicated treatment.
• Participation in another clinical trial with any investigational drug within 14 days prior to study enrollment.
• Patients included in the VEN refractory cohort that have discontinued venetoclax therapy (either monotherapy or combination) due to toxicity or hypersensitivity, including prior history of grade 3/4 TLS during prior VEN exposure
• In dose expansion cohorts, except venetoclax refractory cohort, no prior treatment with SINE compounds, another XPO1 inhibitor, or BCL-2 inhibitors.
• Active GVHD requiring calcineurin inhibitors or steroid dosing ≥ 10mg/day prednisone (or equivalent) or \< 3 months from allogenic hematopoietic cell transplant (HCT).
• Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral.
• Major surgery within 2 weeks of first dose of study drug.
• Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety.
• Unstable cardiovascular function:
• Symptomatic ischemia, or
• Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia therapy are excluded; 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
• Congestive heart failure (CHF) of NYHA Class ≥3, or
• Myocardial infarction (MI) within 3 months.

Sponsors & Collaborators

• Sanjay Mohan: lead
• Karyopharm Therapeutics Inc: collaborator
• AbbVie: collaborator

Study Sites (4)

Roswell Park Cancer Center

Buffalo, New York, 14263, United States

Location

University Hospitals of Cleveland

Cleveland, Ohio, 44106, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-8565, United States

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin

Interventions

venetoclax; selinexor

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Leukemia; Hematologic Diseases

Study Officials

• Sanjay Mohan, MD

  Vanderbilt Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor Investigator

Study Record Dates

• First Submitted: May 16, 2019
• First Posted: May 20, 2019
• Study Start: June 21, 2019
• Primary Completion: September 1, 2024
• Study Completion: September 1, 2024
• Last Updated: October 26, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)