Cabozantinib + Durvalumab +/- Tremelimumab for Gastrointestinal Cancers

(CAMILLA Trial)

Overseen By Anwaar Saeed

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Raed Al-Rajabi

Must not be taking: Immunosuppressants, Anticoagulants

Disqualifiers: Autoimmune disorders, Active infection, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

117 Participants Needed

Trial Summary

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. ^{1 2 3 4 5}

Is 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. ^{4 5 6 7 8}

How 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. ^{2 4 5 7 9}

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.

Research Team

Anwaar Saeed

Principal Investigator

University of Pittsburgh

Eligibility 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).

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.

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

Treatment Details

Interventions

• Cabozantinib
• Durvalumab
• Tremelimumab

Trial Overview 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.

Participant Groups

Group I: Cabozantinib plus Durvalumab plus Tremelimumab (Hepatocellular carcinoma cohort) Experimental Treatment 3 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 Treatment 2 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 Treatment 2 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 Treatment 2 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

Who Is Running the Clinical Trial?

Raed Al-Rajabi

Lead Sponsor

Trials

1

Recruited

120+

Anwaar Saeed

Lead Sponsor

Trials

5

Recruited

240+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Findings from Research

In the phase 3 POSEIDON study involving 1013 treatment-naïve patients with metastatic non-small-cell lung cancer (NSCLC), the combination of tremelimumab, durvalumab, and chemotherapy significantly improved overall survival and progression-free survival compared to chemotherapy alone.

Patients receiving the combination treatment also experienced a longer time to deterioration in quality of life and various symptoms, indicating better overall health status compared to those on chemotherapy, supporting its use as a first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). Garon, EB., Cho, BC., Luft, A., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In the phase 3 MYSTIC study involving 488 treatment-naïve patients with metastatic non-small-cell lung cancer, durvalumab alone or in combination with tremelimumab showed significant improvements in patient-reported outcomes (PROs) compared to chemotherapy, particularly in reducing fatigue and appetite loss.

Patients receiving durvalumab-containing treatments experienced a longer time to deterioration in quality of life and physical functioning, indicating that these treatments may help maintain better overall well-being without negatively impacting quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-Reported Outcomes with Durvalumab With or Without Tremelimumab Versus Standard Chemotherapy as First-Line Treatment of Metastatic Non-Small-Cell Lung Cancer (MYSTIC). Garon, EB., Cho, BC., Reinmuth, N., et al.[2022]

In a study of 113 patients with chemotherapy-refractory gastric or gastroesophageal junction cancer, the combination of durvalumab and tremelimumab showed low overall response rates, with the highest at 15.8% for the combination therapy in the third-line treatment group.

Despite the low efficacy, the study did not identify any new safety concerns, and it suggests that using a tumor-based IFNγ gene signature could be a promising approach to enhance treatment responses in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma. Kelly, RJ., Lee, J., Bang, YJ., et al.[2021]

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

In a phase Ib trial involving 35 patients with advanced gastrointestinal cancers, the combination of cabozantinib and durvalumab showed a tolerable safety profile with no dose-limiting toxicities and a 34% rate of grade 3/4 treatment-related adverse events.

The treatment demonstrated potential efficacy, with an objective response rate of 30% and a disease control rate of 83.3%, particularly in patients with a PD-L1 combined positive score (CPS) ≥5, who experienced better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. Saeed, A., Park, R., Dai, J., et al.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

Tremelimumab shows linear pharmacokinetics with a two-compartment model, and its clearance varies depending on whether it is used as monotherapy or in combination with durvalumab, with a 16% increase in clearance for monotherapy and a 17% decrease for combination therapy over one year.

Factors like higher body weight and lower albumin levels lead to higher drug clearance, but no dosage adjustments are needed, as a flat dose of 75 mg provides similar exposure to the weight-based dosing of 1 mg/kg in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. Hwang, M., Chia, YL., Zheng, Y., et al.[2023]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON). [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

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]

4. United States pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

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]

9. England pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance. [2023]