MEDI4736 + AZD9150/AZD5069 for Head & Neck Cancer

Recruiting at 45 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AstraZeneca

Must not be taking: Steroids, Chemotherapy

Disqualifiers: Second malignancy, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

340 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications, but you must complete any previous cancer-related treatments before enrolling. There is a washout period (time without taking certain medications) of 21 days or 5 half-lives for chemotherapy before starting the study.

What data supports the effectiveness of the drug combination MEDI4736, AZD9150, and AZD5069 for head and neck cancer?

The research mentions that immune checkpoint inhibitors like nivolumab, which target the PD-1/PD-L1 axis similar to MEDI4736, have shown clinical benefits in head and neck cancer by improving survival and quality of life. This suggests that MEDI4736 might also be effective in treating head and neck cancer. ^{1 2 3 4 5}

How does the drug combination MEDI4736 + AZD9150/AZD5069 differ from other treatments for head and neck cancer?

The combination of MEDI4736, AZD9150, and AZD5069 is unique because it targets multiple pathways involved in cancer growth and immune response, potentially offering a novel approach compared to standard chemoradiation therapies. This combination may provide an alternative for patients with resistance to existing treatments, although specific details about its mechanism in head and neck cancer are not directly available from the provided research. ^{1 3 6 7 8}

What is the purpose of this trial?

This multicentre, open-label, Phase 1b/2 study is designed as a 2 part study consisting of a dose-escalation, safety run-in Part A and a dose-expansion Part B

Research Team

David Hong, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with advanced solid tumors or relapsed metastatic squamous cell carcinoma of the head and neck, who have tried ≤3 previous cancer treatments (or none for certain arms), can join. They must be in good physical condition (ECOG PS 0 or 1) with proper organ function and measurable disease. Women of childbearing age and men with partners of childbearing potential must use effective birth control.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

I have had 1 to 3 rounds of chemotherapy to reduce my tumor size.

I have had 3 or fewer previous cancer treatments.

Exclusion Criteria

I have spinal cord compression but haven't needed steroids for it in the last 4 weeks.

I have another cancer type besides SCCHN or was treated for another invasive cancer in the last 3 years.

I have had severe side effects from previous immunotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation (Part A)

Patients with advanced solid malignancies receive escalating doses of AZD9150 or AZD5069 in combination with MEDI4736 to determine maximum tolerated doses (MTDs).

35 days

Multiple visits for dose escalation and monitoring

Dose-expansion (Part B)

Patients with recurrent/metastatic squamous cell carcinoma of the head and neck receive treatment based on the established MTDs to evaluate efficacy and safety.

Up to 12 months

Visits at every even-numbered cycle for assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment until disease progression.

Up to 12 months

Follow-up visits until disease progression

Treatment Details

Interventions

• AZD5069
• AZD9150
• MEDI4736

Trial Overview The trial is testing MEDI4736 combined with either AZD9150 or AZD5069, plus tremelimumab in some cases, to treat advanced cancers. It's a two-part study: Part A finds safe doses; Part B expands on those doses to further assess safety and effectiveness.

Participant Groups

Group I: Part B8: AZD9150 (every other week)+MEDI4736: naive 1L Experimental Treatment 2 Interventions

Patients in Arm B8 will be evaluated for efficacy until disease progression and then followed up for safety and survival

Group II: Part B7: AZD9150+MEDI4736: naiive 1L Experimental Treatment 2 Interventions

Patients in Arm B7 will be evaluated for efficacy until disease progression and then followed up for safety and survival

Group III: Part B6:AZD5069 in naiive patients Experimental Treatment 1 Intervention

Patients in arm B6 will be evaluated for efficacy until disease progression and then allowed to receive additional MEDI4736 and followed for safety and survival

Group IV: Part B5: AZD9150 in naiive patients Experimental Treatment 1 Intervention

Patients in arm B5 will be evaluated for efficacy until disease progression and then allowed to receive additional MEDI4736 and followed for safety and survival

Group V: Part B4:AZD5069+MEDI4736:naiive patients Experimental Treatment 2 Interventions

Patients in arm B4 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.

Group VI: Part B3: AZD9150+MED4736:naiive 2L Experimental Treatment 2 Interventions

Patients in arm B3 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.

Group VII: Part B2:AZD5069+MEDI4736:PDL1 pretreated Experimental Treatment 2 Interventions

Patients in arm B2 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.

Group VIII: Part B1:AZD9150+MEDI4736:PDL1 pretreated Experimental Treatment 2 Interventions

Patients in arm B1 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.

Group IX: Part A7: AZD5069/MEDI4736 Experimental Treatment 2 Interventions

Patients allocated in cohort of arm A7 (AZD5069/MEDI4736) will be evaluated for safety, PK and PD.

Group X: Part A6: AZD9150/MEDI4736 Experimental Treatment 2 Interventions

Patients allocated in cohort of arm A6 (AZD9150/MEDI4736) will be evaluated for safety, PK and PD.

Group XI: Part A5: AZD5069/Treme/MEDI4736 Experimental Treatment 3 Interventions

Patients allocated in cohort of arm A5 (AZD5069/treme/MEDI4736) will be evaluated for DLT and MTD.

Group XII: Part A4: AZD9150/Treme/MEDI4736 Experimental Treatment 3 Interventions

Patients allocated in cohort of arm A4 (AZD9150/treme/MEDI4736) will be evaluated for DLT and MTD

Group XIII: Part A3: AZD5069/MEDI4736 Experimental Treatment 2 Interventions

Patients allocated in cohort of arm A3 (AZD5069/MEDI4736) will be evaluated for DLT and viability as alternate dosing option for Phase 2 studies

Group XIV: Part A2: AZD5069 / MEDI4736 Experimental Treatment 2 Interventions

Patients allocated in cohort of arm A2 (AZD5069/MEDI4736 will be evaluated for DLT until an MTD is achieved.

Group XV: Part A1: AZD9150 / MEDI4736 Experimental Treatment 2 Interventions

Patients allocated in cohort of arm A1 (AZD9150/MEDI4736 will be evaluated for DLT until an MTD is achieved.

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

MedImmune LLC

Industry Sponsor

Trials

348

Recruited

788,000+

Founded

1988

Headquarters

Gaithersburg, USA

Known For

Biologics research

Top Products

Synagis, FluMist

Dr. Reginald Seeto

MedImmune LLC

Chief Medical Officer since 2008

MD from University of Sydney, B.Sc. from University of Sydney

Peter Greenleaf

MedImmune LLC

Chief Executive Officer since 2006

MBA from St. Joseph’s University, B.S. from Western Connecticut State University

Findings from Research

The maximum tolerated dose (MTD) of paclitaxel given as a 96-hour continuous infusion during accelerated radiotherapy for advanced squamous cell carcinoma of the head and neck was determined to be 100 mg/m², with most patients completing the treatment without severe complications.

While some patients experienced significant side effects like Grade 4 mucositis and febrile neutropenia, all toxicities were reversible, and the treatment showed promising efficacy with complete responses in 8 out of 13 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy of unrespectable head and neck cancer. Machtay, M., Aviles, V., Kligerman, MM., et al.[2019]

The JAVELIN Head and Neck 100 study is a Phase III clinical trial investigating the effectiveness of avelumab, a PD-L1 inhibitor, combined with standard chemoradiotherapy (CRT) for high-risk, locoregionally advanced squamous cell carcinomas of the head and neck.

This study addresses a critical gap in research, as there are currently no prospective studies evaluating immune checkpoint inhibitors in the definitive treatment of nonmetastatic HNSCC, which is important for improving outcomes in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. Yu, Y., Lee, NY.[2020]

The maximally tolerated dose (MTD) of afatinib when combined with carboplatin and paclitaxel for treating head and neck squamous cell carcinoma is determined to be 20 mg daily, as higher doses led to severe toxicities.

In a trial with nine patients, five showed a partial response and two had stable disease after induction chemotherapy, indicating some efficacy of the treatment combination, but caution is advised due to significant adverse effects at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Chung, CH., Rudek, MA., Kang, H., et al.[2018]

References

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

JAK kinase inhibition abrogates STAT3 activation and head and neck squamous cell carcinoma tumor growth. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Unexpected Response to Nivolumab in a "Fast Progressor" Head and Neck Cancer Patient. [2020]

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

A phase I trial of 96-hour paclitaxel infusion plus accelerated radiotherapy of unrespectable head and neck cancer. [2019]

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

ATR inhibition sensitizes HPV- and HPV+ head and neck squamous cell carcinoma to cisplatin. [2021]

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

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. [2020]

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

Replication Stress Leading to Apoptosis within the S-phase Contributes to Synergism between Vorinostat and AZD1775 in HNSCC Harboring High-Risk TP53 Mutation. [2021]

7. Netherlands pubmed.ncbi.nlm.nih.gov

AZD4547 targets the FGFR/Akt/SOX2 axis to overcome paclitaxel resistance in head and neck cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. [2018]