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

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
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

Conditions
-----------------
Neoplasm Metastasis

Intervention / Treatment
-----------------
* Drug: CC-90003


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Eligible study subjects in Part 1 and Part 2 must be 18 years or older 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 Eligible study subjects must have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 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: Subjects with symptomatic or unstable CNS metastases Subjects with a history of recent (within 28 days) systemic therapy for their underlying malignancy Subjects who have had surgery/radiotherapy within 2 weeks prior to start of study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1 CC-90003<br>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<br>* CC-90003 PO once daily<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Melanoma, Thyroid carcinomas, Pancreatic ductal Adenocarcinomas, Non -small cell lung cancer [NSCLC], Maximum Tolerated Dose, Solid Tumors, Locally Advanced Tumors, Metastatic Solid Tumors, Relapsed or refractory, BRAFV600 or RAS-mutated solid tumors, Colorectal Carcinomas Papillary