Colorectal Cancer, Gastroesophageal Cancer, Renal Cell Carcinoma
Conditions
Keywords
colorectal cancer, gastroesophageal cancer, renal cell carcinoma, gevokizumab, bevacizumab, modified FOLFOX6, FOLFIRI, ramucirumab, paclitaxel, cabozantinib, CRC, GEC, RCC, VPM087
Brief summary
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.
Interventions
DRUGGevokizumab
60 mg/mL concentration; administered intravenously (IV)
DRUGBevacizumab
25 mg/mL concentration; administered IV
DRUGModified FOLFOX6
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 \[50 mg/mL concentration; administered IV\]
DRUGFOLFIRI
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 \[50 mg/mL concentration; administered IV\]
DRUGRamucirumab
10 mg/mL concentration; administered IV
DRUGPaclitaxel
6 mg/mL concentration; administered IV
DRUGCabozantinib
60 mg tablet; administered orally
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: For All Cohorts: * Adult ≥ 18 years old. * 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. * Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. * Adequate bone marrow and organ function per defined criteria in the protocol. * Recovered from acute laboratory and clinical toxicities of prior anti cancer treatment to NCI CTCAE v5.0 grade ≤1 at time of screening, except alopecia and amenorrhea. For Cohort A: • First line metastatic colorectal adenocarcinoma. For Cohort B: • Second line metastatic colorectal adenocarcinoma that has progressed on prior line of chemotherapy administered for metastatic disease and which must include a fluoropyrimidine and oxaliplatin. For Cohort C: • Second line metastatic gastroesophageal adenocarcinoma 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 (per central laboratory assessment). * 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 (per central laboratory assessment). Key
Exclusion criteria
For All Cohorts: * Currently receiving any of the prohibited medications or has contraindications as outlined in the 'Contraindications' to SOC regimen components. * 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1a/b (Cohorts A and B): Change in high-sensitivity C-reactive protein (hs-CRP) after first dose of gevokizumab monotherapy | Baseline, Day 15 | Log scale change of hs-CRP at Day 15 from baseline |
| Part 1b (Safety run-in): Number of dose limiting toxicities (DLTs) [Cohort C and Cohort D] | First 4 weeks of combination treatment | 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. |
| Part 1b (Safety run-in): Number of DLTs [Cohort A and Cohort B] | First 6 weeks of combination treatment | 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. |
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort A subjects at RDE level] | At 15 months | 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. |
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort B subjects at RDE level] | At 9 months | 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. |
| Part 2 (Expansion) and Part 1b (Safety run-in): Progression free survival (PFS) rate [Cohort C subjects at RDE level] | At 6 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) per investigator assessment using RECIST v1.1 | Up to 5 years | 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 |
| Duration of response (DOR) per investigator assessment using RECIST v1.1 | Up to 5 years | 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 |
| Disease Control Rate (DCR) per investigator assessment using RECIST v1.1 | Up to 5 years | DCR is defined as the proportion of subjects with a BOR of CR, PR, or stable disease (SD), according to RECIST 1.1. |
| Overall survival (OS) | Up to 5 years | OS is defined as the time from date of first dose of study treatment to date of death due to any cause. |
| PFS by baseline hs-CRP category using RECIST 1.1 [Cohort A and B at RDE level] | Up to 5 years | 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. |
| PFS for subjects from Part 1b at doses other than RDE level (Cohort A and Cohort B) | Up to 5 years | 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. |
| Number of patients with anti-drug antibodies for gevokizumab in the combination regimens | Up to 5 years | Incidence of immunogenicity for gevokizumab |
Countries
Australia, Belgium, Canada, Chile, Czechia, Germany, Israel, Italy, Japan, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed