Cabozantinib + Durvalumab +/- Tremelimumab for Gastrointestinal Cancers
(CAMILLA Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Raed Al-Rajabi
Must not be taking: Immunosuppressants, Anticoagulants
Disqualifiers: Autoimmune disorders, Active infection, Hypertension, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The investigators propose to evaluate the safety of drug combinations in patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies. Finding effective novel therapies for patients with advanced gastric cancer and other GI malignancies is an area of great unmet need. The investigators believe that modulating the tumor microenvironment with biologic agents like cabozantinib will have synergistic effect when combined with checkpoint-based immunotherapeutics like durvalumab in this patient population. This is a phase I/II, open label, multi-cohort trial looking at safety, tolerability and efficacy endpoints.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, certain medications like immunosuppressive drugs and some anticoagulants are not allowed, so it's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the drug combination of Cabozantinib, Durvalumab, and Tremelimumab for gastrointestinal cancers?
Research shows that the combination of durvalumab and tremelimumab has been beneficial for patients with solid tumors, and in some studies, it improved survival in lung cancer. Durvalumab is also approved for certain bladder cancers, indicating its potential effectiveness in treating various cancers.
12345Is the combination of Cabozantinib, Durvalumab, and Tremelimumab safe for treating gastrointestinal cancers?
The combination of Cabozantinib and Durvalumab has shown a tolerable safety profile in patients with advanced gastrointestinal cancers, with no dose-limiting toxicities observed. However, when Durvalumab is combined with Tremelimumab, there is a higher incidence of severe side effects, such as reduced appetite and diarrhea, compared to Durvalumab alone.
45678How is the drug combination of Cabozantinib, Durvalumab, and Tremelimumab unique for gastrointestinal cancers?
This drug combination is unique because it combines Cabozantinib, which targets cancer cell growth, with Durvalumab and Tremelimumab, which are immune checkpoint inhibitors that help the immune system attack cancer cells. This approach is novel for gastrointestinal cancers, as it leverages both direct cancer cell inhibition and immune system activation.
24579Eligibility Criteria
Adults over 18 with certain advanced gastrointestinal cancers, including stomach and liver cancer, who have progressed after standard treatments or are intolerant to them. Participants must be able to swallow tablets, not have major organ dysfunction, agree to contraception if of childbearing potential, and not have a history of severe allergies or reactions to the study drugs.Inclusion Criteria
I agree to use effective birth control during and for 6 months after the study.
My cancer is confirmed as stomach or gastroesophageal junction cancer.
I weigh more than 66 lbs (30 kg).
+15 more
Exclusion Criteria
I haven't had any major abdominal issues like fistulas or obstructions in the last 6 months.
My cancer has spread to my digestive system.
My stomach or esophagus veins are treated and stable for 6 months.
+27 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive Cabozantinib and Durvalumab, with or without Tremelimumab, in 28-day cycles
12 months
Monthly visits for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 months
Open-label extension (optional)
Participants may opt into continuation of treatment long-term
Long-term
Participant Groups
The trial is testing the combination of Cabozantinib (a drug that targets tumor environment) with Durvalumab (an immunotherapy), plus or minus Tremelimumab (another immunotherapy). It's an early-phase trial assessing safety and how well these drugs work together in treating gastroesophageal and other GI cancers.
4Treatment groups
Experimental Treatment
Group I: Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort)Experimental Treatment3 Interventions
Cabozantinib
* By mouth (PO) once daily on days 1-28 of every 28 day cycle
* Dose will be 40mg
Durvalumab \*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle
Tremelimumab
\*Single dose of 300mg intavenous (IV) infusion on day 1 of cycle 1
Group II: Cabozantinib plus Durvalumab (Hepatocellular carcinoma cohort)Experimental Treatment2 Interventions
Cabozantinib
* By mouth (PO) once daily on days 1-28 of every 28 day cycle
* Dose will be 40mg
Durvalumab
\*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle
Group III: Cabozantinib plus Durvalumab (Gastric & esophageal cancer cohort)Experimental Treatment2 Interventions
Cabozantinib
* By mouth (PO) once daily on days 1-28 of every 28 day cycle
* Dose will be 40mg
Durvalumab
\*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle
Group IV: Cabozantinib plus Durvalumab (Colorectal cancer cohort)Experimental Treatment2 Interventions
Cabozantinib
* By mouth (PO) once daily on days 1-28 of every 28 day cycle
* Dose will be 40mg
Durvalumab
\*Flat dose of 1500mg intravenous (IV) Infusion on day 1 of every 28 day cycle
Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:
🇪🇺 Approved in European Union as Cabometyx for:
- Renal cell carcinoma
- Hepatocellular carcinoma
🇺🇸 Approved in United States as Cabometyx for:
- Renal cell carcinoma
- Hepatocellular carcinoma
🇨🇦 Approved in Canada as Cabometyx for:
- Renal cell carcinoma
- Hepatocellular carcinoma
🇯🇵 Approved in Japan as Cabometyx for:
- Renal cell carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UPMC Hillman Cancer CenterPittsburgh, PA
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Who Is Running the Clinical Trial?
Raed Al-RajabiLead Sponsor
Anwaar SaeedLead Sponsor
AstraZenecaIndustry Sponsor
ExelixisIndustry Sponsor
References
Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). [2023]In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs).
Durvalumab: First Global Approval. [2022]Intravenous durvalumab (Imfinzi™; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD-1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab ± tremelimumab is under phase III clinical trials in urothelial carcinoma, non-small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma.
Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). [2022]The phase 3 MYSTIC study of durvalumab ± tremelimumab versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC) patients with tumor cell (TC) programmed cell death ligand 1 (PD-L1) expression ≥ 25% did not meet its primary endpoints. We report patient-reported outcomes (PROs).
Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma. [2021]This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.
Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors.
Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. [2023]This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.
Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]Background: Recently, the combination of durvalumab and tremelimumab, two immune checkpoint inhibitors, for the treatment of different types of cancers has been considered; however, its overall effects, including its safety, are still unclear and need to be further investigated. Objectives: The aim of the present systematic review and meta-analysis was to investigate the safety and tolerability of this combination of drugs. Methods: A systematic review of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, was conducted by employing online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. The selection of eligible publications was made following a staged screening and selection process. The software RevMan 5.4 was used to run the quantitative analysis and forest plots, while the Cochrane tool was employed for risk of bias assessment. Results: From the retrieved 157 results, 9 randomized controlled trials involving 3060 patients were included. By comparing the combination of durvalumab and tremelimumab vs. durvalumab monotherapy, it was observed that: adverse events (AEs) ≥ Grade 3 incidence was 32.6% (536/1646) vs. 23.8% (336/1414) (Z = 2.80; p = 0.005; risk ratio (RR) = 1.44), reduced appetite incidence was 10.8% (154/1427) vs. 8.3% (108/1305) (Z = 2.26; p = 0.02; RR = 1.31), diarrhea was reported in 15.6% (229/1473) vs. 8.1% (110/1352) (Z = 5.90; p
Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. [2022]Efficacy of immune checkpoint inhibitors (ICI) as monotherapy in 2nd line treatment for gastric or gastro-oesophageal junction (GEJ) adenocarcinoma is low, with no evaluation of efficacy and safety of ICI combined with chemotherapy. The DURIGAST PRODIGE 59 study is a randomised, multicentre, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI + Durvalumab +/- Tremelimumab as 2nd line treatment of patients with advanced gastric/GEJ adenocarcinoma. Here, we report data from the safety run-in phase with FOLFIRI Durvalumab (arm A) or FOLFIRI Durvalumab and Tremelimumab (arm B). Among the 11 patients included, 63.6% experienced at least one grade 3-4 adverse events (AEs) related to the treatment, most frequently neutropenia (36.4%). There was only one immune-related AE (grade 2 hyperthyroidism). Ten serious AEs were described among six patients, but only two were related to the treatment, due to the chemotherapy. One seizure epilepsy related to a brain metastasis was observed, but was not related by the investigator to the treatment. However, the Independent Data Monitoring Committee recommended brain imaging at inclusion. This safety run-in phase demonstrates an expected safety profile of FOLFIRI with Durvalumab +/- Tremelimumab combination allowing the randomised phase II.
Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. [2023]Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 human monoclonal antibody of the immunoglobulin G2 κ isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics.