Safety and PK Study of CC-90003 in Relapsed/Refractory Solid Tumors

A Phase 1a Multicenter, Open-label Safety, Tolerability and Pharmacokinetic Study of CC-90003, a Selective Extracellular Signal-Regulated Kinase (ERK) Inhibitor, in Subjects With Locally-Advanced or Metastatic, Relapsed, or Refractory BRAF or RAS-Mutated Malignancies

The CC-90003-ST -001 trial is a first-in-man, open-label study in subjects with locally-advanced or wide spread cancers to determine if CC-90003 (an oral medication) can be adequately tolerated with minimal side effects.

Study Overview

• Status: Terminated
• Conditions: Neoplasm Metastasis
• Intervention / Treatment: Drug: CC-90003

Detailed Description

CC-90003-ST -001 is an open-label, multicenter, Phase 1a study in subjects with locally-advanced or metastatic, solid tumors who are intolerant of, resistant to, or have relapsed after at least one line of therapy and for whom no standard therapy exists. The study will be conducted in two parts: Dose Escalation (Part 1) and Cohort Expansion (Part 2). Subjects may continue CC-90003 until progression of their underlying malignancy, the occurrence of intolerable toxicity, or physician/subject decision to discontinue CC-90003. In Part 1, cohorts of subjects with relapsed or refractory solid tumors will receive increasing doses of CC-90003 in order to assess its safety and tolerability, the maximum tolerated dose (MTD), and PK profile. In Part 2, cohorts of subjects with specific tumors that harbor mutations involving the Mitogen -Activated Protein Kinase (MAPK) pathway will receive CC-90003 at or below the MTD until progression of disease, intolerable toxicity, or physician/subject decision to discontinue CC-90003.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3000
    • Peter Maccallum Cancer Centre
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center, Inflammatory Bowel Disease Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Smilow Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer 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. Eligible study subjects in Part 1 and Part 2 must be 18 years or older
2. Eligible study subjects must have histologic or cytologic confirmation of advanced, unresectable or metastatic solid tumors, and have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
3. Eligible study subjects must have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1
4. Eligible study subjects must exhibit acceptable liver, bone marrow, renal and cardiac functions as assessed by laboratory tests, ECG and ECHO or MUGA scan.

Exclusion Criteria:

1. Subjects with symptomatic or unstable CNS metastases
2. Subjects with a history of recent (within 28 days) systemic therapy for their underlying malignancy
3. Subjects who have had surgery/radiotherapy within 2 weeks prior to start of study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 1 CC-90003; CC-90003 by mouth (PO) daily on days 1 -21 of every 28 day cycle; Cycle 1, Days 1 to 28 will constitute the dose limiting toxicity (DLT) assessment period for purposes of non-tolerated dose (NTD) and Maximum Tolerated Dose determination.	Drug: CC-90003; CC-90003 PO once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of the adverse events (type, severity, and incidence) related to CC-	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values regardless of etiology.	Up to 36 months
Dose Limiting Toxicities of CC-90003	Number of participants with dose limiting toxicities during the Dose Escalation Phase	Up to 18 months
Maximum Tolerated Dose (MTD) of CC-90003	The MTD is defined as the highest dose level at which no more than 1 in 6 participants experiences a dose- limiting toxicity (DLT) during the first 28 day cycle of treatment	Up to 36 months
Pharmacokinetics (PK) observed maximum concentration (Cmax)	The maximally observed plasma concentration of CC-90003 (Cmax)	Cycle 1, Day 1, 2, 3 (predose), 8, 11 (predose), 15, 16, , Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
PK-Area under the plasma concentration time curve (AUC)	Area under the plasma concentration -time curve of CC-90003	Cycle 1, Day 1, 2, 3, (predose) 8, 11 (predose), 15, 16, Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
PK-Time to maximal plasma concentration (Tmax)	The time to reach Cmax	Cycle 1, Day 1, 2, 3 (predose) 8, 11 (predose), 15, 16, Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
PK- terminal half-life; t1/2	Terminal phase elimination half-life (t1/2) is calculated as follows: t1/2 =ln(2)/λz, where λz is the first order rate constant associated with the terminal portion of the CC-90003 plasma concentration curve	Cycle 1, Day 1, 2, 3 (predose) 8, 11 (predose), 15, 16, Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
PK-Apparent total body clearance (CL/F)	The apparent total body clearance of CC-90003 from plasma	Cycle 1, Day 1, 2, 3 (predose) 8, 11 (predose) 15, 16, , Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
PK- Apparent Total Volume of Distribution (Vz/F)	PK- Apparent Total Volume of Distribution (Vz/F) During the terminal phase for CC- 90003	Cycle 1, Day 1, 2, 3 (predose) 8, 11 (predose), 15,16, Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation
Accumulation index of CC-90003	Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug	Cycle 1, Day 1, 2, 3 (predose) 8, 11 (predose), 15, 16, Cycle 2, Day 1, Cycle 3, Day 1 and at discontinuation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate based on RECIST 1.1	The proportion of subjects who achieve a best response of CR or PR.	Up to 36 months
Duration of Response	Duration of response is the time from the start of study treatment until the first documentation of an objective response (either CR or PR).	Up to 36 months
Disease Control	The proportion of subjects who achieve a best response of SD (documented at least 56 days after the start of study treatment) PR, or CR	Up to 36 Months
Progression Free Survival	PFS is defined as the time from the start of study treatment until progression (PD) or patient death (any cause), whichever occurs first	Up to 36 months
Overall Survival	Overall survival is defined as the time from start of study treatment until the date of death from any cause.	Up to 36 months

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Gordon Bray, MD, Celgene

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2015
• Primary Completion (Actual): May 3, 2016
• Study Completion (Actual): May 3, 2016

Study Registration Dates

• First Submitted: December 5, 2014
• First Submitted That Met QC Criteria: December 5, 2014
• First Posted (Estimate): December 9, 2014

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: November 14, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Melanoma; Metastatic Solid Tumors; Solid Tumors; Maximum Tolerated Dose; Locally Advanced Tumors; Relapsed or refractory, BRAFV600 or RAS-mutated solid tumors; Colorectal Carcinomas Papillary; Thyroid carcinomas; Pancreatic ductal Adenocarcinomas; Non -small cell lung cancer [NSCLC]
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Neoplasm Metastasis
• Other Study ID Numbers: CC-90003-ST-001