Study of HL-085 and Vemurafinib in Metastatic Colorectal Cancer (mCRC)

Study Overview
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Brief Summary
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The study consists of the two parts, phase IIa and phase IIb.

Detailed Description
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The study consists of the two parts, phase IIa and phase IIb. Phase IIa study is to assess the safety and the antitumor activity in patients with mCRC and to recommend reasonable dosage regimen of HL-085 for phase IIb study. Phase IIb is a pivotal study to evaluate HL-085 plus Vemurafenib in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting.

Official Title
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A Phase Ⅱ, Multicenter Open-label Study to Investigate the Efficacy and Safety of HL-085 Combined With Vemurafenib in Patients With Metastatic Colorectal Cancer (mCRC)

Conditions
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CRC

Intervention / Treatment
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* Drug: HL-085
* Drug: Vemurafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent prior to enrollment； Adults 18 years of age or older, male or female; Histologically- or cytologically-confirmed CRC that is metastatic disease, and a) progression of disease or intolerance after line 1 or line 2 therapy，or inappropriate for line 1 therapy (for phase Ⅱa); b) progression of disease or intolerance after line 1 or line 2 therapy (for phase Ⅱb); Patient must have measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST version 1.1); Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; Life expectancy ≥ 3 months; Able to take the medicine orally; Adequate bone marrow and organ function. Exclusion Criteria: Prior treatment with any RAS inhibitors, RAF inhibitors, or MEK inhibitors; History or screening evidence of retinal diseases; Impaired cardiovascular function or clinically significant cardiovascular and cerebrovascular diseases; Previous or current neuromuscular diseases that is associated with CK elevation (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, rhabdomyolysis syndrome); Impaired liver function, defined as Child-Pugh Class B or C; Toxicity has not recovered to grade 0 or 1 from prior anticancer therapy (except for alopecia, pigmentation, and grade 2 chemotherapy-related neurotoxicity); Use of any medications or foods that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 within 7 days prior to the start of study treatment or during the study period, , drugs with a narrow therapeutic window for CYP1A2 metabolism.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: phase IIa: HL-085 in Subjects With BRAF V600E-Mutated CRC<br>12mg BID HL-085 | Drug: HL-085<br>* 12mg BID HL-085<br>|
| Experimental: phase IIa: HL-085+Vemurafenib in Subjects With BRAF V600E-Mutated CRC<br>12mg BID HL-085+720mg BID Vemurafenib | Drug: HL-085<br>* 12mg BID HL-085<br>Drug: Vemurafenib<br>* 720mg BID Vemurafenib<br>* Other names: ZELBORAF;|
| Experimental: phase IIa: HL-085+Vemurafenib in Subjects With RAS or other BRAF-Mutated or MEK1/2-Mutated CRC<br>12mg BID HL-085+720mg BID Vemurafenib | Drug: HL-085<br>* 12mg BID HL-085<br>Drug: Vemurafenib<br>* 720mg BID Vemurafenib<br>* Other names: ZELBORAF;|
| Experimental: phase IIb: HL-085+Vemurafenib in Subjects With BRAF V600E-Mutated CRC<br>12mg BID HL-085+720mg BID Vemurafenib | Drug: HL-085<br>* 12mg BID HL-085<br>Drug: Vemurafenib<br>* 720mg BID Vemurafenib<br>* Other names: ZELBORAF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR（by investigator） | Phase IIa：ORR per the RECIST version 1.1，defined as the number of patients achieving an overall best response of CR or partial response (PR) divided by the total number of patients | up to 12 months | 
| ORR（by ICR） | Phase Ⅱb：ORR per the RECIST version 1.1，defined as the number of patients achieving an overall best response of CR or partial response (PR) divided by the total number of patients | up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS（by investigator） | Phase IIa：PFS，defined as the time from first dose to the earliest documented disease progression or death due to any cause | up to 12 months | 
| PFS（by ICR） | Phase IIb：PFS，defined as the time from first dose to the earliest documented disease progression or death due to any cause | up to 12 months | 
| DOR（by investigator） | Phase IIa：DOR，Duration of response is defined as subjects who show a confirmed clinical response (CR) or partial response (PR), the time from first documented evidence of CR or PR until the first documented sign of disease progression or death | up to 12 months | 
| DOR（by ICR） | Phase IIb：DOR，Duration of response is defined as subjects who show a confirmed clinical response (CR) or partial response (PR), the time from first documented evidence of CR or PR until the first documented sign of disease progression or death | up to 12 months | 
| DCR（by investigator） | Phase IIa：Proportion of subjects with response defined as CR, PR, and SD throughout the study from subjects first dose to disease progression or death | up to 12 months | 
| DCR（by ICR） | Phase IIb：Proportion of subjects with response defined as CR, PR, and SD throughout the study from subjects first dose to disease progression or death | up to 12 months | 
| OS | OS is defined as the time from the date of taking drugs to the date of death due to any cause | up to 24 months | 
| Number of Adverse Events | Number of Treatment-Related Adverse Events as Assessed by CTCAE v5.0 will be counted | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic colorectal cancer (mCRC), HL-085, Vemurafenib