AZD0022 + Cetuximab for Solid Tumors

(ALAFOSS-01 Trial)

Recruiting at 36 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: Herbal medications, CYP3A4/5 drugs

Disqualifiers: Uncontrolled conditions, ILD, brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

430 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in-human, modular, Phase I/IIa, open-label, multi-centre study to assess the safety, tolerability, PK, and preliminary efficacy of AZD0022 monotherapy in combination with other anti-cancer agents in participants with tumours harbouring a KRASG12D mutation.

Will I have to stop taking my current medications?

The trial requires that you stop taking any herbal medications and certain other medications that affect liver enzymes (CYP3A4/5). You may also need to stop other cancer treatments a few weeks before starting the trial.

What data supports the effectiveness of the drug AZD0022 + Cetuximab for solid tumors?

Cetuximab, one of the components of the treatment, has shown some effectiveness in treating non-small-cell lung cancer and colorectal cancer by targeting the epidermal growth factor receptor (EGFR). In particular, it has been approved for use in colorectal cancer and has shown a small benefit in overall survival for certain lung cancer patients, especially those with high EGFR expression. ^{1 2 3 4 5}

What safety data exists for the treatment AZD0022 + Cetuximab for Solid Tumors?

Cetuximab, used in various cancers, commonly causes skin issues, diarrhea, and tiredness. Rarely, it can lead to serious lung problems, as seen in a fatal case of lung disease. Generally, it is well-tolerated when combined with chemotherapy. ^{2 4 6 7 8}

How is the drug AZD0022 + Cetuximab different from other treatments for solid tumors?

The combination of AZD0022 and Cetuximab is unique because it targets the epidermal growth factor receptor (EGFR) in solid tumors, potentially offering a new approach for patients who may not respond well to existing treatments. Cetuximab is already used in various cancers, but combining it with AZD0022 could enhance its effectiveness, especially in tumors with high EGFR expression. ^{2 3 4 5 9}

Eligibility Criteria

This trial is for adults with certain cancers (like lung, pancreatic, or colorectal cancer) that have a specific genetic change called KRASG12D mutation. Participants should be able to receive the treatments and follow the study procedures.

Inclusion Criteria

My cancer is confirmed to be advanced or has spread.

I can provide a formalin-fixed, paraffin-embedded tumor sample.

Participants must have at least one measurable target lesion per RECIST v1.1

Exclusion Criteria

I am not taking any herbal medications.

I had radiation for cure ≤ 4 weeks ago or palliative radiation ≤ 2 weeks ago.

I have been treated with a KRAS inhibitor before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive AZD0022 monotherapy or in combination with Cetuximab to determine the maximum tolerated dose

Part of a 2-year study

Dose Optimisation

Participants receive AZD0022 monotherapy or in combination with Cetuximab to optimize dosing

Part of a 2-year study

Potential Efficacy Expansion

Participants receive AZD0022 monotherapy or in combination with Cetuximab to assess preliminary efficacy

Part of a 2-year study

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AZD0022
• Cetuximab

Trial Overview The study is testing AZD0022 alone and combined with other cancer drugs like Cetuximab. It's an early-stage trial to see how safe it is, how the body processes it, and if it works against these cancers.

Participant Groups

Group I: Module 2 Part C. Potential Efficacy Expansion Experimental Treatment 2 Interventions

AZD0022 in combination with Cetuximab

Group II: Module 2 Part B. Dose Optimisation Experimental Treatment 2 Interventions

AZD0022 in combination with Cetuximab

Group III: Module 2 Part A. Dose Escalation Experimental Treatment 2 Interventions

AZD0022 in combination with Cetuximab

Group IV: Module 1 Part C. Potential Efficacy Expansion Experimental Treatment 1 Intervention

AZD0022 monotherapy

Group V: Module 1 Part B. Food Effect Cohort Experimental Treatment 1 Intervention

AZD0022 monotherapy

Group VI: Module 1 Part B. Dose Optimisation Experimental Treatment 1 Intervention

AZD0022 monotherapy

Group VII: Module 1 Part A. Dose Escalation Experimental Treatment 1 Intervention

AZD0022 monotherapy

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

Findings from Research

Cetuximab has demonstrated significant efficacy in treating metastatic colorectal cancer, achieving a partial response in 10.8% of patients receiving it alone and 22.9% when combined with irinotecan, based on a Phase III trial involving 329 patients.

The drug is generally well tolerated, with common side effects like acnelike rash and hypersensitivity reactions, but the lack of reliable predictive markers for patient selection remains a challenge for its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Wong, SF.[2022]

Cetuximab shows modest efficacy as a single-agent treatment for metastatic colorectal cancer (CRC) in patients without KRAS mutations, and it can improve overall and progression-free survival when combined with irinotecan in first-line therapy.

The identification of KRAS mutations serves as a negative predictive biomarker, helping to avoid unnecessary toxicity in patients who are unlikely to benefit from cetuximab, thus enhancing the drug's clinical utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of patients with colorectal cancer. Garrett, CR., Eng, C.[2018]

Cetuximab, an anti-cancer drug that targets the epidermal growth factor receptor (EGF-R), can cause acneiform eruptions as a secondary side effect in patients with adenocarcinoma.

The skin reactions, characterized by folliculitis, responded well to topical treatments like benzoyl peroxide and erythromycin gel, indicating that these side effects can be effectively managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cases of acneiform eruption induced by inhibitor of epidermal growth factor receptor. Gencoglan, G., Ceylan, C.[2018]

Cetuximab, an anti-EGF receptor monoclonal antibody, showed no dose-limiting toxicities in Phase I studies and was well-tolerated, with common side effects including skin toxicity, diarrhea, and fatigue.

While Phase III trials indicated only a small overall survival benefit when cetuximab was added to chemotherapy, a subgroup analysis suggested a significant survival advantage in patients with high EGF receptor expression, potentially paving the way for its use in advanced non-small-cell lung cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in non-small-cell lung cancer. Carillio, G., Montanino, A., Costanzo, R., et al.[2018]

In a phase 3 trial involving 938 patients with advanced non-small-cell lung cancer (NSCLC), the addition of cetuximab to pemetrexed chemotherapy did not significantly improve progression-free survival compared to pemetrexed alone, with median survival times of 2.9 months versus 2.8 months, respectively.

Patients receiving cetuximab experienced a higher rate of serious adverse events (41% vs. 29% in the pemetrexed-only group), leading to a recommendation against the use of cetuximab in combination with chemotherapy for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. Kim, ES., Neubauer, M., Cohn, A., et al.[2020]

Cetuximab is an effective monoclonal antibody that targets the epidermal growth factor receptor, showing significant clinical efficacy in treating colorectal cancer (CRC) either alone or in combination with chemotherapy.

The combination of cetuximab with chemotherapy is well tolerated, with minimal overlapping toxicities, making it a crucial treatment option for patients with metastatic CRC who do not respond to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. Mahtani, RL., Macdonald, JS.[2022]

Cetuximab demonstrated antitumor activity in patients with metastatic colorectal carcinoma (CRC) who were resistant to standard treatments, achieving a response rate of approximately 12.4% in a study of 346 patients.

The treatment was generally well tolerated, with a high incidence of acneiform rash (82.9%), which correlated with better treatment efficacy, while EGFR mutations and gene amplification did not significantly influence the response to cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Lenz, HJ., Van Cutsem, E., Khambata-Ford, S., et al.[2022]

Cetuximab, a monoclonal antibody used to treat various cancers, can cause serious side effects, including interstitial lung disease, as demonstrated in a case where a patient developed this condition within the first 4 weeks of treatment and ultimately died.

This case emphasizes the need for healthcare professionals to be aware of the potential for early and fatal pulmonary complications associated with cetuximab, which are not commonly reported in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of fatal cetuximab-induced interstitial lung disease during the first weeks of treatment. Shablak, A., Conn, A.[2021]

Cetuximab, a monoclonal antibody targeting EGFR, is less effective in gastric cancer compared to other cancers, and this study explores the underlying mechanisms of this resistance.

The research found that the Cbl-b protein, an E3 ubiquitin ligase, plays a role in regulating EGFR levels and that silencing Cbl-b can enhance EGFR expression, potentially increasing the sensitivity of gastric cancer cells to cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cbl-b regulates the sensitivity of cetuximab through ubiquitin-proteasome system in human gastric cancer cells. Yu, P., Fan, Y., Qu, X., et al.[2018]

References

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

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of patients with colorectal cancer. [2018]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Two cases of acneiform eruption induced by inhibitor of epidermal growth factor receptor. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Cetuximab in non-small-cell lung cancer. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract. [2022]

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

Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. [2022]

8. France pubmed.ncbi.nlm.nih.gov

A case of fatal cetuximab-induced interstitial lung disease during the first weeks of treatment. [2021]

9. Cyprus pubmed.ncbi.nlm.nih.gov

Cbl-b regulates the sensitivity of cetuximab through ubiquitin-proteasome system in human gastric cancer cells. [2018]