A Safety and Efficacy Study of CC-122 in Combination With Nivolumab in Subjects With Unresectable Hepatocellular Carcinoma (HCC)

Study Overview
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Brief Summary
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CC-122-HCC-002 is a Phase 1/2 dose escalation and expansion clinical study of CC-122 in combination with nivolumab in subjects with unresectable hepatocellular carcinoma (HCC) who have progressed after or were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy.

Detailed Description
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Study population included subjects who had progressed after or were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy. The dose escalation part of the study was designed to explore three dose levels of CC-122 to identify the recommended phase 2 dose (RP2D) to be used in the expansion phase. Approximately 20 subjects were to be enrolled in the dose escalation part of the study. Subjects could be treated for up to 2 years, or until progression of disease, unacceptable toxicity, subject/physician decision, withdrawal of consent, death. Safety follow up until 28 days after CC122 treatment and 90 days after nivolumab treatment. RECIST 1.1 criteria was used to determine response. Survival follow up until death, withdrawal of consent, or the study closes. Subjects were permitted to continue treatment beyond progression (TBP) if they continue to meet protocol criteria, had stable performance status, had clinical benefit, other treatment options were discussed. A separate ICF was signed to continue TBP. During the dose escalation phase, CC-122 was administered orally 5 consecutive days out of 7 (5 days on/2 days off weekly) on Days 1 to 5, 8 to 12, 15 to 19 and 22 to 26 of each 28-day cycle. Once the RP2D for dosing of CC-122 in combination with nivolumab was defined, expansion (Phase 2) would start. A modified 3+3 dose escalation design was used to identify the initial toxicity of the combination. Up to six subjects were concurrently enrolled into a dose level. Decisions as to which dose level to enroll a new subject were based on the number of subjects enrolled and evaluable, the number of subjects experiencing DLTs, and the number of subjects enrolled but who are not yet evaluable for toxicity in the current cohort at the time of new subject entry. A Safety Review Committee (SRC) comprised of investigators participating in the study made dose escalation decisions based on these criteria. After completion of the Dose Escalation Phase, the Dose Expansion Phase of the study did not proceed due to the changing landscape in the treatment of HCC. There were no additional safety concerns or safety signals identified in the dose escalation phase of the study.

Official Title
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A Phase 1/2, MultiCenter, Open-label, Dose Finding Study to Assess the Safety, Tolerability and Preliminary Efficacy of CC-122 in Combination With Nivolumab in Subjects With Unresectable Hepatocellullar Carcinoma (HCC) Following First Line Treatment Failure

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: CC-122
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy the following criteria to be enrolled in the study: Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF) Subject has a confirmed pathologic diagnosis of Hepatocellular carcinoma (HCC) according to the American Association for the Study of Liver Diseases (AASLD) Guidelines. Subjects who have progressed after or were intolerant to no more than 2 previous systemic therapies for unresectable HCC, or are naïve to systemic therapy. Subject has at least one measurable lesion according to RECIST 1.1. Subject has a life expectancy of ≥ 12 weeks Subject has an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 Subject has adequate hematologic function and adequate hepatic function at screening Exclusion Criteria: The presence of any of the following will exclude a subject from enrollment: Subject has received more than 2 previous systemic therapies for Hepatocellular carcinoma (HCC). Subject has received previous treatment with any anti-PD-1 (Programmed death 1) or anti-PD-L1 (PD-1 ligand receptor) antibody

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-122 with Nivolumab<br>CC-122 orally 5/7 days with nivolumab Intravenously (IV) 3mg/kg every 2 weeks. Cohorts of up to 6 subjects per dose level until Recommended Phase 2 dose (RP2D). | Drug: CC-122<br> <br> Drug: Nivolumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) | During dose escalation, the DLT assessment period is defined as Days 1 to 28 of Cycle 1 including the predose assessments specified for Day 1 of Cycle 2. A DLT is defined as any of the following toxicities occurring within the DLT assessment window unless the event can clearly be determined to be unrelated to the drug. | 28 days | 
| Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs) | During dose escalation, the TEAE phase 1 assessment period is defined as Days 1 to 28 of Cycle 1 including the predose assessments specified for Day 1 of Cycle 2. Number of participants who experienced a TEAE during the course of the study. | From first dose up to 28 days (CC-122) or 90 days (nivolumab) post-last dose (up to 2 years) | 
| Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | ORR is is defined as the number and percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR). | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) by RECIST 1.1 | DCR is is defined as the number and percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) or stable disease (SD). | up to 2 years | 
| Duration of Response (DoR) by RECIST 1.1 | Duration of response is measured from the date the criterion is first met for CR/PR using RECIST 1.1 rules (whichever is first recorded) until the first date when progressive disease using RECIST 1.1 is documented or death occurred. | up to 2 years | 
| Progression-Free Survival (PFS) by RECIST 1.1 | Progression-Free Survival (PFS) is defined as the time from the first dose date of study drug until tumor progression or death, whichever occurs first. A subject who has neither progressed nor died or who progresses or dies after an extended lost-to-follow up time (two or more missed assessments) is censored on the date of last adequate tumor assessment. Subjects without valid baseline or post-baseline tumor assessments are censored on their first dose date. Median and the 2-sided 95% confidence interval (CI) are based on Kaplan-Meier estimate of progression-free survival and time to progression using both observed and censored data. | up to 2 years | 
| Overall Survival (OS) by RECIST 1.1 | Overall Survival (OS) is measured as the time from the first dose of study drug to death from any cause. Participants who have no death reported are censored at the last contact date the participant is known to be alive. Median and the 2-sided 95% confidence interval (CI) are based on Kaplan-Meier estimate of progression-free survival and time to progression using both observed and censored data. | up to 2 years | 
| Time to Progression (TTP) by RECIST 1.1 | Time to Progression (TTP) is defined as the time from the first dose date of study drug until tumor progression; TTP does not include death. The censoring rules are the same as PFS except that deaths without progression are censored at last adequate tumor assessment. Median and the 2-sided 95% confidence interval (CI) are based on Kaplan-Meier estimate of progression-free survival and time to progression using both observed and censored data. | up to 2 years | 
| Maximum Observed Concentration (Cmax) | Blood was collected according to intensive and sparse sampling strategies to estimate the population pharmacokinetic (PK) of CC-122 when administered in combination with nivolumab. | 28 days | 
| Area Under the Concentration Time Curve (AUC) | Blood was collected according to intensive and sparse sampling strategies to estimate the population pharmacokinetic (PK) of CC-122 when administered in combination with nivolumab. | 28 days | 
| Time to Maximum Concentration (Tmax) | Blood was collected according to intensive and sparse sampling strategies to estimate the population pharmacokinetic (PK) of CC-122 when administered in combination with nivolumab. | 28 days | 
| Terminal Half-life (T-HALF) | Blood was collected according to intensive and sparse sampling strategies to estimate the population pharmacokinetic (PK) of CC-122 when administered in combination with nivolumab. | 28 days | 
| Apparent Volume of Distribution (Vz/F) | Blood was collected according to intensive and sparse sampling strategies to estimate the population pharmacokinetic (PK) of CC-122 when administered in combination with nivolumab. | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CC-122, Nivolumab, Hepatocellular Carcinoma, Phase 1/2, Safety