Gevokizumab With Standard of Care Anti-cancer Therapies for Metastatic Colorectal, Gastroesophageal, and Renal Cancers

Study Overview
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Brief Summary
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This study will determine the pharmacodynamically-active dose of gevokizumab and the tolerable dose of gevokizumab in combination with the standard of care anti-cancer therapy in patients with metastatic colorectal cancer, metastatic gastroesophageal cancer and metastatic renal cell carcinoma, and the preliminary efficacy of gevokizumab in combination with the SOC anti-cancer therapy in subjects with mCRC and mGEC.

Official Title
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Phase Ib Study of Gevokizumab in Combination With Standard of Care Anti-cancer Therapies in Patients With Metastatic Colorectal Cancer, Gastroesophageal Cancer and Renal Cell Carcinoma

Conditions
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Colorectal Cancer, Gastroesophageal Cancer, Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Gevokizumab
* Drug: Bevacizumab
* Drug: Modified FOLFOX6
* Drug: FOLFIRI
* Drug: Ramucirumab
* Drug: Paclitaxel
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic disease not amenable to potentially curative surgery and with available archival tumor tissue or fresh tumor tissue biopsy. Presence of at least 1 measurable lesion assessed by CT and/or MRI according to RECIST 1.1. For Cohort A: - First line metastatic colorectal cancer. For Cohort B: - Second line metastatic colorectal cancer that has progressed on prior chemotherapy administered for metastatic disease and which must include a fluoropyrimidine and oxaliplatin. For Cohort C: - Second line metastatic gastroesophageal cancer that has progressed on prior line of chemotherapy administered for metastatic disease, and which must include a platinum agent and fluoropyrimidine doublet. For Cohort D: - Second or third line metastatic renal cell carcinoma with a clear-cell component and has received one or two lines of treatment for metastatic disease that included an anti-angiogenic agent for at least 4 weeks with radiologic progression on that treatment. For subjects starting from Part 1a in Cohorts A and B: Serum hs-CRP at screening ≥ 10 mg/L. Not requiring immediate initiation of anti-cancer therapy per investigator's best judgement. For subjects starting from Part 2 in Cohort C: - Serum hs-CRP at screening ≥ 10 mg/L. Exclusion Criteria: For All Cohorts: Currently receiving any of the prohibited medications or has contraindications as outlined in the protocol. Symptomatic brain metastases or brain metastases that require directed therapy (such as focal radiotherapy or surgery). Suspected or proven immunocompromised state, or infections (as defined in the protocol). Conditions that have a high risk of clinically significant bleeding after administration of anti-VEGF agents. Clinically significant, uncontrolled or recent (within last 6 months) cardiovascular disease. For Cohort D: Concomitant medications, herbal supplements, and/or fruits and their juices that are known as strong inhibitors or inducers of CYP3A4/5, and medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5. Impairment of GI function or GI disease that may significantly alter the absorption of cabozantinib. Other protocol-defined inclusion/exclusion criteria may apply

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: 1st line colorectal cancer<br>Treatment for 1st line metastatic colorectal cancer (mCRC) with Gevokizumab, modified FOLFOX6, bevacizumab | Drug: Gevokizumab<br>* 60 mg/mL concentration; administered intravenously (IV)<br>* Other names: VPM087;Drug: Bevacizumab<br>* 25 mg/mL concentration; administered IV<br>Drug: Modified FOLFOX6<br>* Oxaliplatin [5 mg/mL concentration; administered IV], leucovorin [10 mg/mL concentration; administered IV] (or levoleucovorin [10 mg/mL concentration; administered IV]), and 5-fluorouracil [50 mg/mL concentration; administered IV]<br>* Other names: oxaliplatin, leucovorin, 5-fluorouracil;|
| Experimental: Cohort B: 2nd line colorectal cancer<br>Treatment for 2nd line mCRC with Gevokizumab, FOLFIRI, bevacizumab | Drug: Gevokizumab<br>* 60 mg/mL concentration; administered intravenously (IV)<br>* Other names: VPM087;Drug: Bevacizumab<br>* 25 mg/mL concentration; administered IV<br>Drug: FOLFIRI<br>* Irinotecan [20 mg/mL concentration; administered IV], leucovorin [10 mg/mL concentration; administered IV] (or levoleucovorin [10 mg/mL concentration; administered IV]), and 5-fluorouracil [50 mg/mL concentration; administered IV]<br>* Other names: irinotecan, leucovorin, 5-fluorouracil;|
| Experimental: Cohort C: 2nd line gastroesophageal cancer<br>Treatment for 2nd line metastatic gastroesophageal cancer (mGEC) with Gevokizumab, paclitaxel, ramucirumab | Drug: Gevokizumab<br>* 60 mg/mL concentration; administered intravenously (IV)<br>* Other names: VPM087;Drug: Ramucirumab<br>* 10 mg/mL concentration; administered IV<br>Drug: Paclitaxel<br>* 6 mg/mL concentration; administered IV<br>|
| Experimental: Cohort D: 2nd or 3rd line renal cell carcinoma<br>Treatment for 2nd or 3rd line metastatic renal cell carcinoma (mRCC) with Gevokizumab, cabozantinib | Drug: Gevokizumab<br>* 60 mg/mL concentration; administered intravenously (IV)<br>* Other names: VPM087;Drug: Cabozantinib<br>* 60 mg tablet; administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1a (Dose finding): Change in high-sensitivity C-reactive protein (hs-CRP) after first dose of gevokizumab monotherapy | Log scale change of hs-CRP at Day 15 from baseline | Baseline, Day 15 | 
| Part 1b (Safety run-in): Number of dose limiting toxicities (DLTs) [Cohort C and Cohort D] | DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the beginning of treatment with gevokizumab in combination with the SOC anti-cancer therapies and meets any of the protocol specified criteria. | First 4 weeks of combination treatment | 
| Part 1b (Safety run-in): Number of DLTs [Cohort A and Cohort B] | DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the beginning of treatment with gevokizumab in combination with the SOC anti-cancer therapies and meets any of the protocol specified criteria. | First 6 weeks of combination treatment | 
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort A subjects at RDE level] | PFS rate is defined as the percentage of participants who have not progressed or died due to any cause within a specified timeframe after study treatment initiation. Progression will be assessed per investigator assessment using RECIST v1.1. | At 15 months | 
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort B subjects at RDE level] | PFS rate is defined as the percentage of participants who have not progressed or died due to any cause within a specified timeframe after study treatment initiation. Progression will be assessed per investigator assessment using RECIST v1.1. | At 9 months | 
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort C subjects at RDE level] | PFS rate is defined as the percentage of participants who have not progressed or died due to any cause within a specified timeframe after study treatment initiation. Progression will be assessed per investigator assessment using RECIST v1.1. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) per investigator assessment using RECIST v1.1 | ORR is defined as the proportion of subjects with best overall response (BOR) of complete response (CR) or partial response (PR), according to RECIST 1.1 | Up to 5 years | 
| Duration of response (DOR) per investigator assessment using RECIST v1.1 | Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria | Up to 5 years | 
| Disease Control Rate (DCR) per investigator assessment using RECIST v1.1 | DCR is defined as the proportion of subjects with a BOR of CR, PR, or stable disease (SD), according to RECIST 1.1. | Up to 5 years | 
| Overall survival (OS) | OS is defined as the time from date of first dose of study treatment to date of death due to any cause. | Up to 5 years | 
| PFS by baseline hs-CRP category using RECIST 1.1 [Cohort A and B at RDE level] | PFS is defined as the time from the date of first dosing of study drug to the date of the first documented progression or death due to any cause. | Up to 5 years | 
| PFS for subjects from Part 1b at doses other than RDE level (Cohort A and Cohort B) | PFS is defined as the time from the date of first dosing of study drug to the date of the first documented progression or death due to any cause. | Up to 5 years | 
| Serum concentration of gevokizumab, as monotherapy and in the combination regimens | To characterize the pharmacokinetics of gevokizumab therapy | Up to 5 years | 
| Serum concentration of bevacizumab | To characterize the pharmacokinetics of bevacizumab therapy | Up to 5 years | 
| Serum concentration of ramucirumab | To characterize the pharmacokinetics of ramucirumab therapy | Up to 5 years | 
| Serum concentration of irinotecan | To characterize the pharmacokinetics of irinotecan therapy | Up to 3 months | 
| Serum concentration of paclitaxel | To characterize the pharmacokinetics of paclitaxel therapy | Up to 3 months | 
| Serum concentration of cabozantinib | To characterize the pharmacokinetics of cabozantinib therapy | Up to 3 months | 
| Number of patients with anti-drug antibodies for gevokizumab in the combination regimens | Incidence of immunogenicity for gevokizumab | Up to 5 years | 
| Number of patients with anti-drug antibodies for bevacizumab in the combination regimens | Incidence of immunogenicity for bevacizumab | Up to 5 years | 
| Number of patients with anti-drug antibodies for ramucirumab in the combination regimens | Incidence of immunogenicity for ramucirumab | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CRC, colorectal cancer, gastroesophageal cancer, renal cell carcinoma, gevokizumab, bevacizumab, modified FOLFOX6, FOLFIRI, ramucirumab, paclitaxel, cabozantinib, GEC, RCC, VPM087