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

• ClinicalTrials.gov Identifier: NCT02223598
• Recruitment Status: Terminated
• First Posted: August 22, 2014
• Last Update Posted: February 27, 2018
• Sponsor: Cleave Biosciences, Inc.
• Information provided by (Responsible Party): Cleave Biosciences, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Lymphoid Hematological Malignancies; Relapsed and Refractory Multiple Myeloma	Drug: CB-5083; Drug: Dexamethasone	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 25, 2014
• Actual Primary Completion Date: July 26, 2017
• Actual Study Completion Date: July 26, 2017

Arms and Interventions

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: CB-5083; Drug: Dexamethasone
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

Outcome Measures

Primary Outcome Measures :

1. To determine the dose limiting toxicities (DLTs) of oral CB-5083 in subjects with lymphoid hematological malignancies [ Time Frame: Dose Escalation Stage - the first 28 days of treatment (Cycle 1) with CB-5083 ]
2. To determine the pharmacokinetic (PK) profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the AUC [ Time Frame: 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 ]
3. To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Cmax [ Time Frame: 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 ]
4. To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Cmin [ Time Frame: 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 ]
5. To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the Tmax [ Time Frame: 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 ]
6. To determine the PK profile of oral CB-5083 in subjects with lymphoid hematological malignancies by measuring the T1/2 [ Time Frame: 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 ]
7. 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 [ Time Frame: Dose Expansion Stage - from day 1 of Cycle 1 through 28 days after the patient's last cycle of treatment ]
8. To confirm the safety and tolerability of oral CB-5083 administered to subjects with relapsed/refractory DLBCL or Waldenstrom Macroglobulinemia at the MTD [ Time Frame: Dose Expansion Stage - from day 1 of Cycle 1 through 28 days after the patient's last cycle of treatment ]

Secondary Outcome Measures :

1. To assess the pharmacodynamic (PD) effects of CB-5083 in peripheral blood cells and cancer cells [ Time Frame: Dose Escalation and Dose Expansion Stages - days 1, 2, 4 and 5 of Cycle 1 ]
2. To further asses the PK profile of oral CB-5083 in subjects by measuring the AUC [ Time Frame: 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 ]
3. To further asses the PK profile of oral CB-5083 in subjects by measuring the Cmax [ Time Frame: 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 ]
4. To further asses the PK profile of oral CB-5083 in subjects by measuring the Cmin [ Time Frame: 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 ]
5. To further asses the PK profile of oral CB-5083 in subjects by measuring the Tmax [ Time Frame: 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 ]
6. To further asses the PK profile of oral CB-5083 in subjects by measuring the T1/2 [ Time Frame: 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 ]
7. To evaluate preliminary efficacy of oral CB-5083 in subjects, using standard response criteria [ Time Frame: Dose Expansion Stages - at the end of each 28 day cycle of treatment ]

Other Outcome Measures:

1. To assess the predictive value of potential baseline biomarkers for clinical trial subject enrichment strategies [ Time Frame: Dose Expansion Stages - within 28 days before day 1 of Cycle 1 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

University of California, San Francisco

San Francisco, California, United States, 94143

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Maryland

RCCA MD

Bethesda, Maryland, United States, 20817

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Cedars Cancer Centre, McGill University Health Centre

Montreal, Quebec, Canada, H4A 3J1

Sponsors and Collaborators

Cleave Biosciences, Inc.

More Information

• Responsible Party: Cleave Biosciences, Inc.
• ClinicalTrials.gov Identifier: NCT02223598
• Other Study ID Numbers: CLC-102
• First Posted: August 22, 2014
• Last Update Posted: February 27, 2018
• Last Verified: June 2017

Keywords provided by Cleave Biosciences, Inc.:

Lymphoid Hematological Malignancies

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms; Hematologic Neoplasms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Neoplasms by Site; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents