A Phase 1 Study Evaluating CB-5083 in Subjects With Lymphoid Hematological Malignancies (CLC-102)

A Phase 1, Dose-Escalation/Dose-Expansion Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamic Effects of Orally Administered CB-5083 in Subjects With Lymphoid Hematological Malignancies

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.

Study Overview

• Status: Terminated
• Conditions: Lymphoid Hematological Malignancies; Relapsed and Refractory Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone; Drug: CB-5083

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Cedars Cancer Centre, McGill University Health Centre
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • RCCA MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females ≥18 years of age at the time of signing the consent form.

2. 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:

3. Must have a documented diagnosis of relapsed and refractory multiple myeloma defined by the International Myeloma Working Group (IMWG) criteria.

4. 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.

5. 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:

6. Must have histologically confirmed DLBCL that is relapsed or refractory to previous therapy.
7. Must have ≥1 measurable disease sites as defined by standard Lugano classification.

8. 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:

9. Must have a confirmed diagnosis of WM as defined by the Second International Workshop, with a clinical indication for treatment.
10. Must have measurable disease, defined as presence of serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of each institution's normal value is required.

11. Must have relapsed/refractory disease after receiving 1 or more lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor (eg ibrutinib) if approved by the local health authority and commercially accessible.

    All Arms:

12. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.

13. Adequate bone marrow function without transfusion or growth factor support, defined as:

    • Absolute neutrophil count ≥ 1,000/μL;
    • Platelet count ≥ 50,000/μL;
    • Hemoglobin ≥ 8.0 g/dL

14. Adequate organ function defined as:

    • Serum creatinine ≤ 1.5 mg/dL or creatinine clearance > 45 mL/min according to Cockcroft-Gault formula; (If creatinine clearance calculated from a 24-hour urine sample is ≥45 mL/min, the subject will qualify for the study).
    • Serum total bilirubin ≤ 2.0 mg/dL (34.2 μmol/L); or > 3.0 × upper limit of normal (ULN) for subjects with hereditary benign hyperbilirubinemia
    • AST (SGOT) ≤ 3 × the ULN;
    • ALT (SGPT) ≤ 3 × the ULN;
15. Subjects who are fertile agree to use an effective barrier method of birth control (ie, latex condom, diaphragm, cervical cap, etc) to avoid pregnancy. Female subjects need a negative serum or urine pregnancy test within 7 days of study enrollment (applies only if subject is of childbearing potential. Non-childbearing is defined as ≥ 1 year postmenopausal or surgically sterilized).
16. Willing and able to provide written Informed Consent and adhere to study procedures.

Exclusion Criteria:

1. 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.
2. Clinically active central nervous system (CNS) cancer involvement. Imaging to exclude CNS involvement not required.
3. 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;
4. Use of any anti-cancer drug therapy within 14 days prior to Baseline (within 28 days for monoclonal antibodies [eg anti-CD38]).
5. Use of any investigational agent within 28 days prior to Baseline.
6. 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.
7. Radiotherapy within 14 days prior to Baseline.
8. Major surgery within 6 weeks prior to Baseline. The subject must have recovered from surgery and be without current complications of infection or dehiscence.
9. Peripheral autologous stem cell transplant within 12 weeks prior to Baseline; prior allogeneic transplants within 16 weeks or chronic use of immunosuppressants.
10. 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.
11. 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.
12. Cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 12 weeks prior to Baseline.
13. 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.
14. Grade 3 or 4 eye disorder at study entry, unless stable and longstanding (>3 months) and unlikely to interfere with protocol-required ophthalmology assessments.
15. A condition that is expected to require concomitant use of any medication listed as prohibited while on study.
16. Is a pregnant or lactating female.
17. Has any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the subject inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation - CB-5083; 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
Experimental: Dose Expansion - CB-5083, Dexamethasone; 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: Dexamethasone; Drug: CB-5083
Experimental: Dose Expansion - CB-5083; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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
To further asses the PK profile of oral CB-5083 in subjects by measuring the T1/2	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 evaluate preliminary efficacy of oral CB-5083 in subjects, using standard response criteria	Dose Expansion Stages - at the end of each 28 day cycle of treatment

Other Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Cleave Biosciences, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2014
• Primary Completion (Actual): July 26, 2017
• Study Completion (Actual): July 26, 2017

Study Registration Dates

• First Submitted: August 15, 2014
• First Submitted That Met QC Criteria: August 21, 2014
• First Posted (Estimate): August 22, 2014

Study Record Updates

• Last Update Posted (Actual): February 27, 2018
• Last Update Submitted That Met QC Criteria: February 23, 2018
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Lymphoid Hematological Malignancies
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms by Site; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Neoplasms; Hematologic Neoplasms; Multiple Myeloma; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: CLC-102