Selinexor in Combination With Ixazomib for the Treatment of Advanced Sarcoma

NCT03880123 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: AAAS0199
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The main purpose of this study is to establish a safe and tolerable dose combination (the "maximum tolerated dose") of selinexor and ixazomib when used together for the treatment of patients with certain types of advanced sarcoma. The study will enroll patients with advanced dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma. Future studies to further evaluate the safety and anti-cancer efficacy of this treatment for sarcoma will use the dose combination determined in this study.

Conditions

Liposarcoma; Malignant Peripheral Nerve Sheath Tumors; Alveolar Soft Part Sarcoma; Ewing Sarcoma; Sarcoma

Keywords

Liposarcoma; Malignant Peripheral Nerve Sheath Tumors; Alveolar Soft Part Sarcoma; Ewing Sarcoma; Selinexor; ixazomib; sarcoma; kpt-330

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  To establish the maximum tolerated dose combination for selinexor and ixazomib when used as a combination treatment for patients with dedifferentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma and Ewing sarcoma. The MTD is defined by the time to event continual reassessment method, a model-based dose finding study design.

  Up to 2 years

Secondary Outcomes (1)

• Adverse Event (AE) Rate

  Up to 2 years

Other Outcomes (1)

• Objective Response Rate (ORR)

  Up to 2 years

Study Arms (1)

Selinexor/Ixazomib

EXPERIMENTAL

Patients will receive combination treatment with selinexor and ixazomib. The dose of ixazomib is fixed at 4 mg, whereas several different dose levels of selinexor may be evaluated. No patients will receive a placebo.

Drug: Selinexor; Drug: Ixazomib

Interventions

Selinexor DRUG

Selinexor will be taken orally on Days 1, 8, 15, and 22 of each cycle at the following dose levels (DLs): DL 1: 40 mg; DL 2: 60 mg; DL 3: 80 mg; DL 4: 100 mg The selinexor product is provided as 20 mg tablets in wallet-sized blister packs. Selinexor should be taken together with ixazomib.

Also known as: KPT-330

Selinexor/Ixazomib

Ixazomib DRUG

Ixazomib will be taken orally on Days 1, 8, and 15 of each cycle at the same dose level: 4 mg. The ixazomib product is provided in strengths of 4.0, 3.0, and 2.3 mg capsules as the active boronic acid. Ixazomib should be taken on an empty stomach (no food or drink) at least 1 hour before or at least 2 hours after food.

Also known as: Ninlaro

Selinexor/Ixazomib

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent.
• Age ≥ 14 years
• Body surface area ≥ 1.2 m2
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Histologically confirmed de-differentiated liposarcoma, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma or Ewing sarcoma. Liposarcomas with areas of well-differentiated disease are eligible if there is a biopsy-proven component of dedifferentiated liposarcoma. Pathology is reviewed at Columbia University Medical Center.
• Disease which is locally advanced and unresectable or metastatic. Disease which may be resected but with an associated level of morbidity deemed unacceptable by the treating clinician is considered eligible.
• Measurable disease as assessed by RECIST criteria version 1.1.
• Progression on, or intolerance to, at least one prior systemic regimen for sarcoma (including systemic treatment used in the adjuvant or neoadjuvant settings). For alveolar soft part sarcoma and dedifferentiated liposarcoma, there is no upper limit on the number of prior therapies that may have been received. For Ewing sarcoma and malignant peripheral nerve sheath tumor, patients may have received no more than 3 prior lines of therapy (excluding systemic treatment used in the adjuvant or neoadjuvant settings).
• Acceptable organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥ 1,500/mm3 Hemoglobin ≥ 8.5 g/dL Platelet count ≥ 100,000/mm3 Calculated creatinine clearance \> 30 mL/min Total bilirubin ≤ 1.5 times upper limit of normal Aspartate Transaminase (AST) /Alanine Transaminase (ALT) ≤ 3.0 times upper limit of normal
• Upper limit of normal is defined by the clinical laboratory performing the test.
• Creatinine clearance is obtained using the lean body mass formula (Modified Cockcroft Gault)
• If transaminase elevation and/or bilirubin elevation is attributed to the presence of liver metastases, a total bilirubin ≤ 2.5 times the upper limit of normal and an Aspartate Transaminase (AST) and Alanine Transaminase (ALT) ≤ 2.5 times the upper limit of normal are permissible. Patients with an elevated bilirubin level that is attributed to an inherited disorder, such as Gilbert's disease, may be enrolled at the discretion of the principal investigator.
• Patients may not receive platelet transfusions within 3 weeks of initiating protocol therapy.
• Meet the following criteria regarding contraception:

You may not qualify if:

• Received selinexor or another XPO1 inhibitor previously.
• Received ixazomib or another proteasome inhibitor previously.
• Currently pregnant or lactating.
• Received any systemic anticancer therapy including investigational agents or radiation ≤3 weeks (or ≤5 half-lives of the drug, whichever is longer) prior to registration. Patients must have recovered to grade ≤ 1 or baseline from clinically significant adverse effects associated with prior anti-cancer therapies except for alopecia or controlled endocrinopathies.
• Major surgery within 2 weeks of first dose of study treatment.
• Any serious medical or psychiatric illness, medical condition or organ dysfunction which, in the investigator's opinion, could compromise patient safety or compliance with the protocol.
• Unstable cardiovascular function as defined by:
• Symptomatic ischemia, or
• Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree arterioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or
• Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥3, or
• Myocardial infarction (MI) within 6 months
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. Prophylactic use of antibiotics and/or antivirals is acceptable.
• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positivity.
• History of clinically significant ocular disease manifest by visual defects or disturbances, including those caused by active glaucoma or cataracts, which have not been addressed by surgery or other corrective intervention. If necessary, an opthalmologic exam should be performed at screening.
• Inability to swallow tablets, clinically significant malabsorption syndrome, or any other GI disease or dysfunction that could interfere with absorption of study drugs.

Sponsors & Collaborators

• Matthew Ingham: lead
• Karyopharm Therapeutics Inc: collaborator
• Takeda: collaborator

Study Sites (1)

Columbia University Medical Center

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Liposarcoma; Neurofibrosarcoma; Sarcoma, Alveolar Soft Part; Sarcoma, Ewing; Sarcoma

Interventions

selinexor; ixazomib

Condition Hierarchy (Ancestors)

Neoplasms, Adipose Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neoplasms, Muscle Tissue; Osteosarcoma; Neoplasms, Bone Tissue

Study Officials

• Matthew Ingham, MD

  Columbia University

  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: Assistant Professor of Medicine (Oncology)

Study Record Dates

• First Submitted: March 15, 2019
• First Posted: March 19, 2019
• Study Start: November 1, 2020
• Primary Completion: November 24, 2020
• Study Completion: November 24, 2020
• Last Updated: November 27, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)