A Phase 1 Study Evaluating CB-5083 in Subjects With Lymphoid Hematological Malignancies

NCT02223598 | Terminated Phase 1 DMC

• 1 other identifier: CLC-102
• Study Type: interventional
• Target: 120
• Locations: 2 countries
• Sites: 8

Brief Summary

The purpose of this study is to determine the safety, tolerability, dose limiting toxicities, and maximum tolerated dose of CB-5083 in subjects with lymphoid hematological malignancies.

Conditions

Lymphoid Hematological Malignancies; Relapsed and Refractory Multiple Myeloma

Keywords

Lymphoid Hematological Malignancies

Outcome Measures

Primary Outcomes (8)

• To determine the dose limiting toxicities (DLTs) of oral CB-5083 in subjects with lymphoid hematological malignancies

  Dose Escalation Stage - the first 28 days of treatment (Cycle 1) with CB-5083

• To determine the pharmacokinetic (PK) profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the AUC

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 in the second 28 days (Cycle 2) of treatment with CB-5083

• To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Cmax

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Cmin

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Tmax

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the T1/2

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To confirm the safety and tolerability of oral CB-5083 administered to subjects with relapsed and refractory Multiple Myeloma at the maximum tolerated dose (MTD) at the end of the Dose Escalation Stage

  Dose Expansion Stage - from day 1 of Cycle 1 through 28 days after the patient's last cycle of treatment

• To confirm the safety and tolerability of oral CB-5083 administered to subjects with relapsed/refractory DLBCL or Waldenstrom Macroglobulinemia at the MTD

  Dose Expansion Stage - from day 1 of Cycle 1 through 28 days after the patient's last cycle of treatment

Secondary Outcomes (7)

• To assess the pharmacodynamic (PD) effects of CB-5083 in peripheral blood cells and cancer cells

  Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1

• To further asses the PK profile of oral CB-5083 in subjects by measuring the AUC

  Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To further asses the PK profile of oral CB-5083 in subjects by measuring the Cmax

  Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To further asses the PK profile of oral CB-5083 in subjects by measuring the Cmin

  Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

• To further asses the PK profile of oral CB-5083 in subjects by measuring the Tmax

  Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 and days 1 and 2 of Cycle 2 of treatment with CB-5083

Other Outcomes (1)

• To assess the predictive value of potential baseline biomarkers for clinical trial subject enrichment strategies

  Dose Expansion Stages - within 28 days before day 1 of Cycle 1

Study Arms (3)

Dose Escalation - CB-5083

EXPERIMENTAL

CB-5083 will be administered orally, 4 days on and 3 days off, for 28 day cycles, as a single agent to subjects with lymphoid hematological malignancies

Drug: CB-5083

Dose Expansion - CB-5083, Dexamethasone

EXPERIMENTAL

CB-5083 will be administered orally, 4 days on and 3 days off, for 28 day cycles, as a single agent to subjects with relapsed and refractory multiple myeloma; in addition, subjects who develop progressive disease at the end of Cycle 1, or beyond, may receive their current dose of CB-5083 in combination with oral or IV low dose Dexamethasone (40 mg)

Drug: CB-5083; Drug: Dexamethasone

Dose Expansion - CB-5083

EXPERIMENTAL

CB-5083 will be administered orally, daily, 4 days on and 3 days off, for 28 day cycles, as a single agent to subjects with diffuse large B-cell lymphoma (DLBCL) or Waldenstrom Macroglobulinemia, if such arm is opened, per Sponsor

Drug: CB-5083

Interventions

CB-5083 DRUG

Dose Escalation - CB-5083; Dose Expansion - CB-5083; Dose Expansion - CB-5083, Dexamethasone

Dexamethasone DRUG

Dose Expansion - CB-5083, Dexamethasone

Eligibility Criteria

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

You may qualify if:

• Males and females ≥18 years of age at the time of signing the consent form.
• Dose Escalation Phase: Have a documented diagnosis of a lymphoid hematological malignancy as described by the 2008 World Health Organization (WHO) classification that requires therapy and for which there is no standard of care or standard of care is not expected to be effective. Subjects must not be candidates for anti-tumor regimens known to provide clinical benefit.
• MM Dose Expansion Cohort:
• Must have a documented diagnosis of relapsed and refractory multiple myeloma defined by the International Myeloma Working Group (IMWG) criteria.
• Must have measurable disease defined as:
• Serum M-protein ≥ 0.5g/dL of IgA or ≥ 1 g/dL of IgG, or
• Urine M-protein ≥ 200 mg/24 hr, or
• Involved FLC assay \> 10 mg/dL with abnormal FLC ratio.
• Must have received at least 4 prior therapies, including an alkylating agent (unless not clinically indicated), proteasome inhibitor, an immunomodulatory (IMiD) and CD38 targeted therapy. At least 3 prior therapies where CD38 targeted therapies are not approved, not commercially accessible, contraindicated or refused by subject.
• DLBCL Dose Expansion Arm:
• Must have histologically confirmed DLBCL that is relapsed or refractory to previous therapy.
• Must have ≥1 measurable disease sites as defined by standard Lugano classification.
• Must have received at least 2 prior therapies, including a CD20 targeted therapy, alkylating agent or corticosteroid; subjects who are not eligible for high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) are eligible with exposure to at least 1 prior therapy.
• Waldstrom's Macroglobulinemia Dose Expansion Arm:
• Must have a confirmed diagnosis of WM as defined by the Second International Workshop, with a clinical indication for treatment.

You may not qualify if:

• Subjects with leukemia are excluded, with the exception of chronic lymphocytic leukemia (CLL), who are allowed in the dose escalation phase. Subjects with Burkitt lymphoma, plasma cell leukemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), or amyloidosis are also excluded.
• Clinically active central nervous system (CNS) cancer involvement. Imaging to exclude CNS involvement not required.
• Previous or concomitant malignancy, except for basal-cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the uterine cervix. Subjects with other malignancies are eligible if they have remained disease free for at least 2 years prior to study entry;
• Use of any anti-cancer drug therapy within 14 days prior to Baseline (within 28 days for monoclonal antibodies \[eg anti-CD38\]).
• Use of any investigational agent within 28 days prior to Baseline.
• Presence of clinically significant non-hematological toxicity of prior chemotherapy that has not resolved to ≤ Grade 1 as determined by CTCAE v 4.0, with the exception of alopecia and peripheral neuropathy. Note: Peripheral neuropathy \> Grade 2 plus pain, or Grade 3 or Grade 4 are excluded.
• Radiotherapy within 14 days prior to Baseline.
• Major surgery within 6 weeks prior to Baseline. The subject must have recovered from surgery and be without current complications of infection or dehiscence.
• Peripheral autologous stem cell transplant within 12 weeks prior to Baseline; prior allogeneic transplants within 16 weeks or chronic use of immunosuppressants.
• Active infection requiring systemic therapy, including known human immunodeficiency virus (HIV), acquired immunodeficiency syndrome-related illness, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
• Major cardiac abnormalities as defined but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction within 12 weeks prior to Baseline, Class 3 or higher New York Heart Association (NYHA) congestive heart failure, or severe cardiac insufficiency, persistent (3 consecutive electrocardiograms (ECGs) performed ≥ 5 minutes apart) prolongation of the QTc (Fridericia) interval to \> 480 msec.
• Cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 12 weeks prior to Baseline.
• Major gastrointestinal (GI) disease as defined but not limited to the following: history of inflammatory bowel disease or other illness resulting in chronic diarrhea, known achlorhydria or history of GI surgery that could reduce the acidity of the stomach, acute pancreatitis or cholecystitis within 6 months prior to Baseline, or GI disease that may interfere with the absorption of orally-administered drugs.
• Grade 3 or 4 eye disorder at study entry, unless stable and longstanding (\>3 months) and unlikely to interfere with protocol-required ophthalmology assessments.
• A condition that is expected to require concomitant use of any medication listed as prohibited while on study.

Sponsors & Collaborators

• Cleave Biosciences, Inc.: lead

Study Sites (8)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

RCCA MD

Bethesda, Maryland, 20817, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Cedars Cancer Centre, McGill University Health Centre

Montreal, Quebec, H4A 3J1, Canada

Location

MeSH Terms

Conditions

Recurrence; Multiple Myeloma

Interventions

CB-5083; Dexamethasone

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; 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

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: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 15, 2014
• First Posted: August 22, 2014
• Study Start: August 25, 2014
• Primary Completion: July 26, 2017
• Study Completion: July 26, 2017
• Last Updated: February 27, 2018

Record last verified: 2017-06

Locations

CA (2); US (6)