Adavosertib + Durvalumab for Cancer

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: Immunosuppressives, WEE-1 inhibitors

Disqualifiers: Brain metastases, Autoimmune disorders, Cardiac diseases, others

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

Compensation: Varies

Number of Visits: 1

Duration: 28-day cycles, up to 18 months

56 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, especially those that are sensitive to CYP3A4 enzymes, two weeks before starting the study and during the trial. Herbal preparations must be stopped 7 days before the first dose. If you are on specific cancer treatments, you may need a longer washout period after discussing with the Medical Monitor.

What data supports the effectiveness of the drug combination Adavosertib + Durvalumab for cancer?

Durvalumab, one of the drugs in the combination, has shown effectiveness in treating advanced non-small-cell lung cancer, especially in patients with high PD-L1 expression. It has been approved for use after chemoradiation in locally advanced cases, indicating its potential in combination therapies. ^{1 2 3 4 5}

Is the combination of Adavosertib (AZD1775) and Durvalumab (MEDI4736) generally safe for humans?

Durvalumab (MEDI4736) has shown a manageable safety profile in various cancers, with some side effects like reduced appetite and diarrhea. When combined with other drugs, it can lead to more severe side effects, but it is generally considered tolerable. ^{1 2 3 4 6}

How is the drug Adavosertib + Durvalumab unique for cancer treatment?

Adavosertib + Durvalumab is unique because it combines a cell cycle checkpoint inhibitor (Adavosertib) with an immune checkpoint inhibitor (Durvalumab), potentially enhancing the body's immune response against cancer cells while disrupting their ability to repair DNA damage, which is different from standard chemotherapy or single-agent immunotherapy. ^{7 8 9 10 11}

What is the purpose of this trial?

This study will assess the safety, tolerability, and pharmacokinetics of AZD1775 (adavosertib) given orally in combination with intravenous MEDI4736 (durvalumab). Secondly, the immunogenicity, pharmacodynamics, and preliminary anti-tumour activity will be determined in patients with refractory solid tumours.

Research Team

Manish Patel, M.D.

Principal Investigator

Florida Cancer Specialists

Eligibility Criteria

Adults (≥18 years) with solid tumors that are unresponsive to standard treatments or have no standard care available. Participants must weigh at least 30 kg, be able to consent, and have an ECOG Performance Status of 0-1. They should not be pregnant or breastfeeding, agree to use contraception, and meet specific health criteria including blood counts and organ function tests.

Inclusion Criteria

My solid tumor does not respond to standard treatments or no treatment exists.

Baseline laboratory values within 7 days prior to receiving study drugs: ANC ≥1500/μL, Haemoglobin (HgB) ≥9 g/dL, Platelets ≥100,000/μL, ALT and AST ≤ 2.5 x Upper Limit of Normal, Serum bilirubin within normal limits or ≤ 1.5 x ULN in patients with liver metastases, Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min, Fertile females of child-bearing potential who agree to use adequate contraceptive measures, Male patients must agree to use at least one medically acceptable form of contraception, Predicted life expectancy ≥ 12 weeks, Willing to provide consent for the collection of biological samples, Willingness and ability to comply with study and follow-up procedures

I am fully active or can carry out light work.

Exclusion Criteria

History of primary immunodeficiency

Psychiatric illness or social situations that would limit compliance with study requirements

I haven't had major surgery in the last 28 days or minor surgery in the last 7 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in

AZD1775 (adavosertib) monotherapy lead-in period for pharmacokinetic assessment

7-9 days

1 visit (in-person)

Treatment

Combination treatment with AZD1775 (adavosertib) and MEDI4736 (durvalumab) in various dosing schedules

28-day cycles, up to 18 months

Multiple visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AZD1775
• MEDI4736

Trial Overview The trial is testing the combination of two drugs: AZD1775 (adavosertib), taken orally, and MEDI4736 (durvalumab), given intravenously. It aims to evaluate their safety, how well they're tolerated by patients' bodies, how they affect the body's handling of drugs (pharmacokinetics), immune response effects (immunogenicity), changes in disease indicators (pharmacodynamics), and initial effectiveness against advanced solid tumors.

Participant Groups

Group I: Dose Schedule D Experimental Treatment 2 Interventions

In Schedule D, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) one time per day orally on Days 15-19, and Days 22-26 of a 28-day cycle. In Schedule D there will be a 9-day lead-in period with AZD1775 (adavosertib) being dosed on Days -9 to -5 to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Group II: Dose Schedule C Experimental Treatment 2 Interventions

In Schedule C, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 8-10, Days 15-17, and Days 22-24 of a 28-day cycle. In Schedule C there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 (durvalumab) on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Group III: Dose Schedule B Experimental Treatment 2 Interventions

In Schedule B, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 15-17 and Days 22-24 of a 28-day cycle. In Schedule B there will be a 7-day AZD1775 (adavosertib) lead-in to enable serial PK measurements prior to initiating MEDI4736 on Day 1. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib) consecutive dosing day blocks including the lead-in portion of Schedules B, C, and D. Additional alternative dose levels and/or schedules may also be explored if emerging data suggest these would be more appropriate.

Group IV: Dose Schedule A Experimental Treatment 2 Interventions

In Schedule A, patients will receive MEDI4736 (durvalumab) by intravenous on Day 1, and AZD1775 (adavosertib) twice daily orally on Days 1-5 and Days 15-19 of a 28-day cycle. In all dose schedules, dexamethasone will be administered as an anti-emetic on the first day of the AZD1775 (adavosertib).

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

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Durvalumab, an immunotherapy drug for non-small cell lung cancer (NSCLC), has shown significant activity and acceptable tolerability, especially in patients with at least 25% PD-L1 tumor expression, and has been established as a standard treatment following chemoradiation based on the PACIFIC study results.

While durvalumab is effective in wild-type EGFR and ALK patients, its efficacy is lower in those with EGFR mutations or ALK-positive status, highlighting the need for ongoing research into combination therapies and the management of treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. Mezquita, L., Planchard, D.[2019]

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 study involving 58 patients with advanced squamous non-small-cell lung cancer (sqNSCLC) who had previously progressed on anti-PD-(L)1 therapy, the combination of durvalumab and tremelimumab showed minimal efficacy, with only a 7% response rate in those with primary resistance and no responses in the acquired resistance cohort.

The treatment resulted in a median progression-free survival of about 2 months and an overall survival of approximately 7.6 to 7.7 months, indicating limited effectiveness in overcoming resistance to prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760). Leighl, NB., Redman, MW., Rizvi, N., 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]

Tofacitinib at doses of 3 mg or higher taken twice daily showed significant efficacy in treating active rheumatoid arthritis, with ACR20 response rates reaching up to 71.9% by week 12, compared to 22.0% for placebo.

The treatment was generally well-tolerated, with manageable side effects, the most common being urinary tract infections and diarrhea, indicating a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Fleischmann, R., Cutolo, M., Genovese, MC., et al.[2022]

In a Phase 3 trial involving 797 patients with rheumatoid arthritis who did not respond adequately to methotrexate, tofacitinib (5 or 10 mg twice daily) led to significant improvements in patient-reported outcomes (PROs) after 3 months, which were maintained over 24 months.

Patients receiving tofacitinib reported clinically meaningful enhancements in various aspects of health, including pain and quality of life, compared to those on placebo, with similar improvements observed in patients who switched from placebo to tofacitinib later in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: patient-reported outcomes from the 24-month Phase 3 ORAL Scan study. Strand, V., van der Heijde, D., Tanaka, Y., et al.[2022]

In a study involving 6610 patients with active rheumatoid arthritis, adalimumab was found to be generally well tolerated, with serious infections occurring in only 3.1% of patients, indicating a favorable safety profile.

At 12 weeks, adalimumab demonstrated significant effectiveness, with 69% of patients achieving an ACR20 response, and it was effective both alone and in combination with various DMARDs, including antimalarials and methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Burmester, GR., Mariette, X., Montecucco, C., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. [2018]

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

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Durvalumab for the treatment of non-small cell lung cancer. [2019]

4. 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]

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

Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760). [2023]

6. 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]

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

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. [2022]

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

Efficacy of adalimumab in the treatment of moderate-to-severe psoriasis: A retrospective study of 100 patients in daily practice. [2018]

9. Italy pubmed.ncbi.nlm.nih.gov

Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: patient-reported outcomes from the 24-month Phase 3 ORAL Scan study. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. [2022]

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

Squamous cell carcinoma of the lip associated with adalimumab therapy for ankylosing spondylitis: a case report and review of TNF-α inhibitors and cutaneous carcinoma risk. [2015]