A Phase 1 Study Evaluating CB-5083 in Subjects With Advanced Solid Tumors

NCT02243917 | Terminated Phase 1 DMC

• 1 other identifier: CLC-101
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 6

Brief Summary

This is a multicenter, open-label, Phase 1 study of orally administered CB-5083 in adult subjects with advanced metastatic solid tumors. The study will be conducted in 2 parts: an initial Dose Escalation Phase (Phase 1a) of CB-5083 in subjects with advanced metastatic solid tumors who have progressed or are non-responsive to available therapies and for which no standard therapy exists, followed by a Dose Expansion Phase (Phase 1b) which will include 1 to 4 arms: one arm in subjects with RAS mutated mCRC; optionally, at sponsors discretion, 3 additional arms may be added for subjects with advanced RCC, advanced pNET, or solid tumors with mutations in the RAS-MAPK pathway.

Conditions

Advanced Solid Tumors

Outcome Measures

Primary Outcomes (5)

• Dose Escalation Stage - the dose limiting toxicities (DLTs), using NCI CTCAE v4.0, of oral CB-5083 in subjects with advanced tumors

  the first 28 days of treatment with CB-5083

• Dose Escalation Stage - the pharmacokinetic profile (PK) of oral CB-5083 in subjects with advanced solid tumors; parameters include AUC, Cmax, Tmax and T1/2

  day 1 to day 5 of Cycle 1 and day 1 and day 2 of Cycle 2

• Dose Expansion Stage - safety and tolerability of oral CB-5083 administered to subjects with RAS mutated metastatic colorectal cancer (mCRC) at the RP2D, using NCI CTCAE v4.0

  day 1 of Cycle 1 through 28 days after the subjects's last treatment

• Dose Expansion Stage - safety and tolerability of CB-5083 in subjects with advanced renal-cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET) or solid tumors with RAS-MAPK mutations, if such arms are opened per Sponsor, using NCI CTCAE v4.0

  from day 1 of Cycle 1 through 28 days after the subjects's last treatment

• Food Effect Stage - the effect of a standard meal on the plasma concentration of oral CB-5083 in subjects with advanced solid tumors

  from day 1 of Cycle 1 through day 5 of Cycle 1

Secondary Outcomes (4)

• Dose Escalation Stage - the pharmacodynamic (PD)effects of CB-5083 through the measurement of polyubiquitin accumulation (PUA) in peripheral blood mononuclear cells (PBMCs)

  day 1 through day 5 of Cycle 1

• Dose Expansion Stage - PK and PD profiles of CB-5083; PK parameters to include AUC, Cmax, Tmax and T1/2; PD effects through the measurement of PUA in PBMCs

  day 1 through day 5 of Cycle 1; day 1 and day 2 of Cycle 2 (PK only)

• Dose Expansion Stage - anti-tumor activity in certain subjects, using the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1

  from the pre-study visit though the end of the last cycle on treatment, an expected average of 14 weeks

• Food Effect Stage - safety and tolerability of oral CB-5083 in subjects with advanced solid tumors using NCI CTCAE v4.0, of oral CB-5083

  From day 1 of Cycle 1 through 28 days after the subjects's last treatment

Study Arms (3)

Dose Escalation Stage - CB-5083

EXPERIMENTAL

CB-5083 will be orally administered daily, 4 days on and 3 days off, for 28 day cycles; subjects who have completed at least one cycle may optionally participate in a food effect week, wherein CB-5083 will be orally administered once daily, on days 1 and 4, and thereafter return to the original dosing schedule

Drug: CB-5083

Dose Expansion Stage - CB-5083

EXPERIMENTAL

CB-5083 will be orally administered daily, 4 days on and 3 days off, for 28 day cycles

Drug: CB-5083

Food Effect Stage - CB-5083

EXPERIMENTAL

CB-5083 will be orally administered once daily, on days 1 and 4 of week 1, cycle 1, and orally administered daily, 4 days on and 3 days off, for the remaining 3 weeks of cycle 1; for subsequent 28 day cycles, CB-5083 will be orally administered daily, 4 days on and 3 days off

Drug: CB-5083

Interventions

CB-5083 DRUG

Dose Escalation Stage - CB-5083; Dose Expansion Stage - CB-5083; Food Effect Stage - CB-5083

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;
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤1
• Acceptable bone marrow and organ function at screening as described below:
• ANC ≥ 1,500/µL;
• Platelet count ≥ 100,000/µL;
• Total bilirubin ≤ 1.5 × ULN or ≤ 3.0 × ULN for subjects with hereditary benign hyperbilirubinemia;
• AST (SGOT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases are present);
• ALT (SGPT) ≤ 3 × ULN (≤ 5 × ULN if liver metastases are present);
• Serum creatinine ≤ 1.5 mg/dL or a measured creatinine clearance ³ 60 mL/min according to Cockcroft-Gault formula
• Left ventricular ejection fraction informed (LVEF) ≥ 55%;
• Ability to swallow and retain oral medications;
• Negative serum beta-human Chorionic Gonadotropin (β-hCG) test in women of childbearing potential (WOCBP); Note, subject must agree to use dual barrier contraceptive methods; and
• Willing and able to provide written informed consent and comply with the requirements of the study;
• Phase 1a Dose Escalation only - Histologically confirmed advanced solid tumor for which standard therapy does not exist or is no longer effective
• Food Effect Stage - willing and able to ingest a standard meal

You may not qualify if:

• Any prior treatment (with the exception of somatostatin analogues, which are allowed before and during the study in pNET subjects at the investigator discretion in pNET subjects) such as chemotherapy, immunomodulatory drug therapy, anti-neoplastic hormonal therapy (unless dose has been stable for 3 months prior to Baseline and will remain stable during the study), immunosuppressive therapy, or corticosteroids (unless administered to prevent contrast material reactions during radiographic procedures) received within the past 28 days or 5 half-lives, whichever is shorter;
• Presence of an acute or chronic toxicity resulting from prior chemotherapy, with the exception of alopecia, that has not resolved to ≤ grade 1, as determined by NCI CTCAE v 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html);
• Received radiotherapy within the last 21 days (limited palliative radiation is allowed if ≥ 14 days prior);
• Subjects with primary brain tumors or known central nervous system (CNS) metastases;
• Major surgery \< 28 days from the start of treatment (major surgery is defined as a procedure requiring general anesthesia);
• Minor surgery \<14 days from the start of treatment (insertion of a vascular access device is not considered major or minor surgery);
• Active infection requiring systemic therapy;
• Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness;
• Uncontrolled congestive heart failure, angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug;
• History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of any grade, or persistent prolongation of the QTc (Fridericia) interval to \> 450 msec for males or \> 470 msec for females;
• History of esophageal bleeding due to varices;
• Gastrointestinal disease that may interfere with the absorption of orally-administered drugs;
• History of inflammatory bowel disease or other illness resulting in chronic diarrhea;
• Known achlorhydria or history of gastrointestinal surgery that could reduce the acidity of the stomach;
• Acute pancreatitis or cholecystitis within 6 months prior to Baseline;

Sponsors & Collaborators

• Cleave Biosciences, Inc.: lead

Study Sites (6)

HonorHealth Research Institute

Scottsdale, Arizona, 85258, United States

Location

Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute

Los Angeles, California, 90048, United States

Location

University of California San Francisco

San Francisco, California, 94115, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Winship Cancer Institute of Emory University

Atlanta, Georgia, 30322, United States

Location

University of Pennsylvania, Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Interventions

CB-5083

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: September 15, 2014
• First Posted: September 18, 2014
• Study Start: October 11, 2014
• Primary Completion: August 25, 2017
• Study Completion: August 25, 2017
• Last Updated: February 27, 2018

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)