Phase II Umbrella Study of Novel Anti-cancer Agents in Patients With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy

Study Overview
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Brief Summary
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This is an open-label, multi-centre, umbrella Phase II study in patients with metastatic NSCLC who have progressed on an anti-PD-1/PD-L1 containing therapy. This study is modular in design, allowing initial assessment of the efficacy, safety, and tolerability of multiple treatment arms.

Detailed Description
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This is an open-label, multi-centre, umbrella Phase II study in patients with metastatic non-small cell lung cancer (NSCLC) who have progressed on an anti-programmed cell death-1/anti-programmed cell death ligand 1 (anti-PD-1/PD-L1) containing therapy. This study is modular in design, consisting of a number of treatment cohorts, allowing evaluation of the efficacy, safety, and tolerability of multiple treatment arms. There is currently no established therapy for patients who have received immune checkpoint inhibitors and platinum-doublet therapies, and novel treatments are urgently needed. This protocol has a modular design, with the potential for future treatment arms to be added via protocol amendment.

Official Title
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An Open-Label, Multi-Drug, Biomarker-Directed, Multi-Centre Phase II Umbrella Study in Patients With Non-Small Cell Lung Cancer, Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (HUDSON).

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Durvalumab
* Drug: AZD9150
* Drug: AZD6738
* Drug: Vistusertib
* Drug: Olaparib
* Drug: Oleclumab
* Drug: trastuzumab deruxtecan
* Drug: cediranib
* Drug: AZD6738 (ceralasertib)
* Drug: AZD6738 (ceralasertib)
* Drug: AZD6738 (ceralasertib) (240 mg or 160 mg)
* Drug: AZD6738 (ceralasertib) 7 days monotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: At least 18 years of age at the time of signing the informed consent form. Patient must have histologically or cytologically confirmed metastatic or locally advanced and recurrent NSCLC which is progressing. Patients eligible for second- or later-line therapy, who must have received an antiPD1/PD-L1 containing therapy and a platinum-doublet regimen for locally advanced or metastatic NSCLC either separately or in combination. Prior durvalumab is acceptable. The patient must have had disease progression on a prior line of antiPD1/PD-L1 therapy. ECOG/WHO performance status of 0 to 1, and a minimum life expectancy of 12 weeks. Patient must have at least 1 lesion that can be accurately measured. A previously irradiated lesion can be considered a target lesion if the lesion has clearly progressed. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Exclusion Criteria: Patients whose tumour samples have targetable alterations in EGFR and/or ALK at initial diagnosis are excluded. In addition, patients whose tumour samples are known to have targetable alterations in ROS1, BRAF, MET or RET, are to be excluded. Active or prior documented autoimmune or inflammatory disorders. Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not willing to employ effective birth control. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients, or history of severe hypersensitivity reactions to other monoclonal antibodies. Patient has spinal cord compression or symptomatic brain metastases. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Patients may receive treatment with bisphosphonates or receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors for the treatment of bone metastases. history of active primary immunodeficiency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an open-label, multi-centre, umbrella Phase II study in patients with metastatic NSCLC who have progressed on an anti-PD-1/PD-L1 containing therapy. This study is modular in design, allowing initial assessment of the efficacy, safety, and tolerability of multiple treatment arms. Within each module, there will be treatment cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab + olaparib<br>Durvalumab given in combination with olaparib . | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: Olaparib<br>* Olaparib (AZD2281) given orally at 300 mg BD<br>|
| Experimental: Durvalumab + AZD9150<br>Durvalumab given in combination with AZD9150. | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: AZD9150<br>* AZD9150 given IV at 200mg every other day of a 1-week lead-in period followed by QW<br>|
| Experimental: Durvalumab + AZD6738<br>Durvalumab given in combination with AZD6738. | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: AZD6738<br>* AZD6738 given orally at 240mg twice daily in Cycle 0 Days 1-7, followed by 7 days on treatment in each cycle between Days 22-28<br>|
| Experimental: Durvalumab + vistusertib<br>Durvalumab given in combination with Vistusertib (AZD2014). | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: Vistusertib<br>* Vistusertib (AZD2014) given orally at a dose of 125 mg BD on an intermittent dosing schedule of 2 days on, 5 days off<br>|
| Experimental: Durvalumab + Oleclumab<br>Durvalumab given in combination with Oleclumab | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: Oleclumab<br>* Oleclumab given at dose level 1 for 2 cycles and then dose level 2 thereafter<br>|
| Experimental: durvalumab + trastuzumab deruxtecan<br>durvalumab given in combination with trastuzumab deruxtecan (DS-8201a) | Drug: trastuzumab deruxtecan<br>* Durvalumab given IV at 1120mg Q3W ±2 days for Module 6 only & trastuzumab deruxtecan given at 5.4 mg/kg via IV infusion Q3W ±2 days<br>|
| Experimental: durvalumab + cediranib<br>durvalumab given in combination with cediranib (AZD2171) | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: cediranib<br>* cediranib given orally at 20 mg tablets on an intermittent schedule (5 days on, 2 days off), starting on C1D1<br>|
| Experimental: AZD6738 (ceralasertib) monotherapy<br>AZD6738 (ceralasertib) given as monotherapy | Drug: AZD6738 (ceralasertib)<br>* AZD6738 given at 240 mg twice daily for 14 days on treatment in each 28-day cycle, between Days 1 and 14.<br>|
| Experimental: durvalumab & AZD6738 (ceralasertib)<br>durvalumab given in combination with AZD6738 (D15-D28) | Drug: Durvalumab<br>* Durvalumab given IV at 1500 mg Q4W ±2 days<br>Drug: AZD6738 (ceralasertib)<br>* AZD6738 given orally at 240mg twice daily for 14 days in each 28 day cycle (starting from Cycle 1) between Days 15-28<br>|
| Experimental: durvalumab & AZD6738 (ceralasertib) (240 mg or 160 mg)<br>durvalumab in combination with twice daily 160 mg or 240 mg AZD6738 (D22-D28) | Drug: AZD6738 (ceralasertib) (240 mg or 160 mg)<br>* AZD6738 given orally at 240mg or 160mg twice daily in Cycle 0 Days 1-7, followed by 7 days on treatment in each cycle between Days 22-28<br>|
| Experimental: AZD6738 (ceralasertib) 7 days monotherapy<br>AZD6738 (ceralasertib) monotherapy on D1-7 of every 28 days | Drug: AZD6738 (ceralasertib) 7 days monotherapy<br>* AZD6738 given orally at 240 mg twice daily for 7 days on Day 1-7 in each 28 day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the efficacy of each treatment by evaluation of objective response rate | Endpoint based on Response Evaluation Criteria in Solid Tumours (RECIST 1.1) Objective response rate (ORR) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease control rate (DCR) using RECIST 1.1 assessment for the anti-tumour activity of each therapy. | Assessment of the anti-tumour activity of each therapy. | Through to study completion, up to 3.5 years. | 
| Best percentage change in tumour size using RECIST 1.1 assessment for the anti-tumour activity of each therapy | Assessment of the anti-tumour activity of each therapy. | Through to study completion, up to 3.5 years. | 
| Duration of response (DoR) using RECIST 1.1 assessment for the anti-tumour activity of each therapy. | Assessment of the anti-tumour activity of each therapy. | Through to study completion, up to 3.5 years | 
| Progression free survival (PFS) using RECIST 1.1 assessment for the anti-tumour activity of each therapy. | Assessment of the anti-tumour activity of each therapy. | Through to study completion, up to 3.5 years. | 
| Overall surival (OS) | Assessment of the anti-tumour activity of each therapy. | Through to study completion, up to 4.5 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small cell lung cancer, NSCLC, anti-PD-1/PD-L1, umbrella study, Durvalumab, MEDI4736, Olaparib, AZD2281, AZD9150, AZD6738, Vistusertib, AZD2014, Oleclumab, MEDI9447, Trastuzumab deruxtecan, DS-8201a, cediranib, AZD2171