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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of new drug combinations for individuals with advanced stomach, esophageal, colorectal, or liver cancers. Researchers are investigating whether combining cabozantinib, an oral drug, with durvalumab, an IV immunotherapy, and potentially tremelimumab, another IV drug, can more effectively treat these cancers. The trial is open to those whose cancer has progressed despite other treatments and who have a confirmed diagnosis of one of these cancer types. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of cabozantinib and durvalumab is generally well-tolerated in patients with various cancer types. Studies have found that this combination has a manageable safety profile. Specifically, for patients with advanced liver cancer (hepatocellular carcinoma), cabozantinib proves effective and safe, with dose adjustments made to manage side effects.

For stomach and esophageal cancers, the combination of cabozantinib and durvalumab is also considered safe. Similarly, for colorectal cancer, research suggests that these two drugs together are well-tolerated and may offer benefits.

When tremelimumab is added to cabozantinib and durvalumab for liver cancer, early studies indicate that this triple combination is safe and might provide additional benefits. However, the safety of this combination remains under investigation, as it is a more intensive treatment.

Overall, while these drug combinations are still under investigation, current evidence suggests they are generally safe for humans, with side effects manageable through dose changes or additional care. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Cabozantinib and Durvalumab, with or without Tremelimumab, for gastrointestinal cancers because these treatments offer a novel approach compared to current options. Unlike traditional chemotherapy, Cabozantinib targets specific proteins involved in tumor growth and blood vessel development, potentially slowing cancer progression more effectively. Durvalumab and Tremelimumab are both immune checkpoint inhibitors that help the immune system recognize and attack cancer cells, which is a different mechanism than conventional treatments. This multi-faceted strategy could lead to more effective control of cancer with potentially fewer side effects than existing therapies.

What evidence suggests that this trial's treatments could be effective for gastrointestinal cancers?

Research has shown that using cabozantinib and durvalumab together may help treat various gastrointestinal cancers. In this trial, participants with stomach and esophagus cancers will receive cabozantinib plus durvalumab. Studies found that 30% of these patients experienced a noticeable reduction in cancer size, and 83.3% had their disease stabilized. For those with colon cancer, the same combination led to a 27.6% reduction in cancer size, with 20.7% of patients experiencing partial improvement. Participants with liver cancer will be in separate arms, receiving either cabozantinib plus durvalumab or cabozantinib plus durvalumab and tremelimumab. Using cabozantinib alone or with durvalumab proved effective, with patients living without cancer progression for an average of 5.2 months and an overall survival of 11.5 months. Adding tremelimumab for liver cancer further improved survival rates. These results suggest that these drug combinations could be promising options for patients with these difficult-to-treat cancers. ^{3 6 7 8 9}

Who Is on the Research Team?

Anwaar Saeed

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

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 have not had signs of lung bleeding in the last 3 months.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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 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]

Citations

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Cabozantinib plus durvalumab shows efficacy in subset of ... The 29 patients evaluable for the efficacy analysis had an ORR of 27.6%, confirmed partial response rate of 20.7% and disease control rate of ...

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Can we close the Gap between Potential and Practice? Phase Ib/II Trial Evaluating the Safety, Tolerability and Immunological Activity of Durvalumab (MEDI4736) (Anti-PD-L1) Plus Tremelimumab (Anti- ...