Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck

Study Overview
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Brief Summary
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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

Detailed Description
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The dose-escalation Part A of this study will involve patients with advanced solid malignancies refractory to standard therapy or for which no standard of care regimen currently exists. Approximately 30 evaluable patients per treatment arm (A1 or A2) will be enrolled. A3 will test viability of alternate dosing schedule for AZD5069, A4/A5 will evaluate AZD9150/AZD5069 in fixed dose combination with MEDI4736 and tremelimumab in solid tumors. there may also be safety run in cohorts enrolled (A6/A7) in specific solid tumor types (breast and prostate cancer). Once the maximum tolerated doses (MTDs) for each of the 2 agents (AZD9150/AZD5069)in combination with MEDI4736 have been identified or the maximum doses of each of the 2 agents in combination with MEDI4736 have been reached, the dose expansion Part B of the study would commence. It will be conducted in patients with recurrent and/or metastatic (RM) squamous cell carcinoma of the head and neck (SCCHN). Between 68 and 266 eligible patients will be enrolled and will randomly assigned to 1 of the following 6 treatment arms or non randomized arm B7: Treatment arm B1: AZD9150 in combination with MEDI4736 in patients with prior exposure to anti-PD-(L)1 antibodies Treatment arm B2: AZD5069 in combination with MEDI4736 in patients with prior exposure to anti-PD-(L)1 antibodies Treatment arm B3: AZD9150 in combination with MEDI4736 in patients with no prior exposure to anti-PD-(L)1 antibodies (2L RM SCCHN) Treatment arm B4: AZD5069 in combination with MEDI4736 in patients with no prior exposure to anti-PD-(L)1 antibodies Treatment arm B5: AZD9150 alone in patients with no prior exposure to anti-PD-(L)1 antibodies Treatment arm B6: AZD5069 alone in patients with no prior exposure to anti-PD-(L)1 antibodies Treatment arm B7: (non randomized): AZD9150 in combination with MEDI4736 in patients with no prior exposure to anti-PD-(L)1 antibodies (1L RM SCCHN) Treatment arm B8: (non randomized): AZD9150 (every two weeks) in combination with MEDI4736 in patients with no prior exposure to anti-PD-(L)1 antibodies (1L RM SCCHN)

Official Title
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A Phase 1b/2, Open-Label, Multicentre Study Assessing the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of MEDI4736 in Combination With AZD9150 or AZD5069 in Patients With Advanced Solid Malignancies and Subsequently Comparing AZD9150 and AZD5069 Both as Monotherapy and in Combination With MEDI4736 as Second Line Treatment in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck.

Conditions
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Advanced Solid Tumors & Metastatic Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: AZD9150
* Drug: MEDI4736
* Drug: AZD5069
* Drug: tremelimumab (treme)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female patients must be at least 18 years of age. Has an Eastern Cooperative Oncology Group (ECOG) PS score of 0 or 1. Has measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded) with a minimum size of 10 mm by computerised tomography (CT) scan, except lymph nodes which must have minimum short axis size of 15 mm (CT scan slice thickness no greater than 5 mm in both cases). Indicator lesions must not have been previously treated with surgery, radiation therapy, or radiofrequency ablation unless there is documented progression after therapy. Has undergone ≤3 previous regimens (depending on treatment arm) of cytoreductive therapies including, but not limited to, platinum-based compounds, taxanes, or 5-fluorouracil. for B7 & B8, no prior systemic treatments should have been received for RM SCCHN Adequate organ and marrow function Female subjects of childbearing potential and male subjects with partners of childbearing potential should ensure use of a highly effective method of birth control as defined in study protocol Additional inclusion for part A: Has a histological confirmation of a solid malignancy (other than HCC) that is refractory to standard therapy or for which no standard of care regimen currently exists. Addition inclusion for Part A (A6) Has a histological confirmation of castrate-resistant prostate cancer Additional inclusion for Part B:Has histologically and/or cytologically confirmed SCCHN that is RM and not amendable to curative therapy by surgery or radiation. Squamous cell carcinoma of the head and neck originating from the following sites is eligible: oral cavity, oropharynx, larynx, or hypopharynx. Has at least 1 SCCHN tumour lesion (TL) amenable to biopsy and must have failed, refused, or has been found to be ineligible for least 1 prior platinum-based chemotherapy for RM-SCCHN Additional inclusion criteria for Arms B1 & B2: must have had prior exposure to anti PDL-1 antibody Arms B1-B6: Has undergone 1-3 previous regimens of cytoreductive chemo-therapies Arm B7 & B8: with no prior exposure to anti-PD-(L)1 therapies and have received no prior systemic treatment for RM SCCHN Key Exclusion Criteria: - Spinal cord compression unless asymptomatic and not requiring steroids for at least 4 weeks before the start of study treatment. - Presently has a second malignancy other than SCCHN, or history of treatment for invasive cancer other than SCCHN in the past 3 years. Exceptions are: Previously treated in-situ carcinoma (ie, noninvasive) Cervical carcinoma stage 1B or less Noninvasive basal cell and squamous cell skin carcinoma Radically treated prostate cancer (prostatectomy or radiotherapy) with normal prostate-specific antigen, and not requiring ongoing antiandrogen hormonal therapy Patients must have completed any previous cancer-related treatments before enrolment. Any concurrent chemotherapy [Chemotherapy washout within 21 days or 5 half-lives (whichever is shorter) from enrolment], radiotherapy, immunotherapy, or biologic, or hormonal therapy for cancer excludes the patient (concurrent use of hormones for noncancer-related conditions [eg, insulin for diabetes and hormone replacement therapy] is acceptable), Experiencing CTCAE grade >1 events, experienced immune-related grade ≥3AEs with prior immunotherapy Has active or prior autoimmune disease within the past 2 years Has active or prior inflammatory bowel disease or primary immunodeficiency Undergone an organ transplant that requires use of immunosuppressive treatment Abnormalities in rhythm, conduction or morphology of resting 12-lead ECG uncontrolled comorbid conditions Received a live attenuated vaccine within 30 days of first study dose, unable to take oral medications History of allergic reactions to study compounds or excepients Additional exclusion criteria Part A: Patients with clinically active brain metastases and prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody. Additional exclusion criteria Part B: Patients with brain metastases (known or suspected) Additional exclusion criteria Part B: treatment arms B3, B4, B5, B6, B7 and B8: prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A1: AZD9150 / MEDI4736<br>Patients allocated in cohort of arm A1 (AZD9150/MEDI4736 will be evaluated for DLT until an MTD is achieved. | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Part A2: AZD5069 / MEDI4736<br>Patients allocated in cohort of arm A2 (AZD5069/MEDI4736 will be evaluated for DLT until an MTD is achieved. | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part B1:AZD9150+MEDI4736:PDL1 pretreated<br>Patients in arm B1 will be evaluated for efficacy until disease progression and then followed-up for safety and survival. | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Part B2:AZD5069+MEDI4736:PDL1 pretreated<br>Patients in arm B2 will be evaluated for efficacy until disease progression and then followed-up for safety and survival. | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part B3: AZD9150+MED4736:naiive 2L<br>Patients in arm B3 will be evaluated for efficacy until disease progression and then followed-up for safety and survival. | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Part B4:AZD5069+MEDI4736:naiive patients<br>Patients in arm B4 will be evaluated for efficacy until disease progression and then followed-up for safety and survival. | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part B5: AZD9150 in naiive patients<br>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 | Drug: AZD9150<br>* AZD9150<br>|
| Experimental: Part B6:AZD5069 in naiive patients<br>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 | Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part A3: AZD5069/MEDI4736<br>Patients allocated in cohort of arm A3 (AZD5069/MEDI4736) will be evaluated for DLT and viability as alternate dosing option for Phase 2 studies | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part A4: AZD9150/Treme/MEDI4736<br>Patients allocated in cohort of arm A4 (AZD9150/treme/MEDI4736) will be evaluated for DLT and MTD | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>Drug: tremelimumab (treme)<br>* tremelimumab<br>|
| Experimental: Part A5: AZD5069/Treme/MEDI4736<br>Patients allocated in cohort of arm A5 (AZD5069/treme/MEDI4736) will be evaluated for DLT and MTD. | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>Drug: tremelimumab (treme)<br>* tremelimumab<br>|
| Experimental: Part A6: AZD9150/MEDI4736<br>Patients allocated in cohort of arm A6 (AZD9150/MEDI4736) will be evaluated for safety, PK and PD. | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Part A7: AZD5069/MEDI4736<br>Patients allocated in cohort of arm A7 (AZD5069/MEDI4736) will be evaluated for safety, PK and PD. | Drug: MEDI4736<br>* MEDI4736<br>Drug: AZD5069<br>* AZD5069<br>|
| Experimental: Part B7: AZD9150+MEDI4736: naiive 1L<br>Patients in Arm B7 will be evaluated for efficacy until disease progression and then followed up for safety and survival | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|
| Experimental: Part B8: AZD9150 (every other week)+MEDI4736: naive 1L<br>Patients in Arm B8 will be evaluated for efficacy until disease progression and then followed up for safety and survival | Drug: AZD9150<br>* AZD9150<br>Drug: MEDI4736<br>* MEDI4736<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | After completion of DLT period (35 days) for the maximum dose cohort. A CRM-based approach was used to identify the set of dose combinations where the incidence of DLT was ≤ 33%. The dose with expected DLT incidence closest and below 0.33 at this point was the model estimated MTD. During trial execution, the Safety Review Committee (SRC) determined the MTD. | 35 days | 
| Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | After completion of DLT period (35 days) for the maximum dose cohort. A CRM-based approach was used to identify the set of dose combinations where the incidence of DLT was ≤ 33%. The dose with expected DLT incidence closest and below 0.33 at this point was the model estimated MTD. During trial execution, the Safety Review Committee (SRC) determined the MTD. | 35 days | 
| Part A: Safety and Tolerability in Terms of Adverse Events | Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters | At every treatment and follow up visit until disease progression, an average of 1 year. | 
| Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | proportion of patients who have an objective response at a given visit. ORR will be summarised by treatment group. Objective rate is defined as a CR or PR according to RECIST 1.1. | Assessed at every even-numbered cycles with RECIST until disease progression, up to 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to calculate AUC, we need to have enough PK samples collected to enable AUC estimation. That is why we have a difference in actual AUC calculated number of subjects vs number of subjects participated. | Lead in day -7, AUC from time 0 to 6h (post dose). | 
| Part A and B: AZD9150 Cmax at Lead in Day -7 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Cmax we need to have samples at end of infusion, which was not available for all the subjects in PK analysis set. That is why there is a difference between Cmax calculated number of subjects vs number of subjects participated. | Lead in day -7 | 
| Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to calculate AUC, we need to have enough PK samples collected to enable AUC estimation. That is why we have a difference in actual AUC calculated number of subjects vs number of subjects participated. | Cycle 2 day 1, AUC from time 0 to 6 h post dose | 
| Part A and B: AZD9150 Cmax at Cycle 2 Day 1 |  | Cycle 2 day 1 | 
| Part A and B: AZD5069 AUC0-12h at Lead in Day -7 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to calculate AUC, we need to have enough PK samples collected to enable AUC estimation. That is why we have a difference in actual AUC calculated number of subjects vs number of subjects participated. | Lead in day -7, AUC from time 0 to 12h post dose | 
| Part A and B: AZD5069 Cmax at Lead in Day -7 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Cmax we need to have samples at Tmax, which was not available for all the subjects in PK analysis set. That is why there is a difference between Cmax calculated number of subjects vs number of subjects participated. | Lead in day -7 | 
| Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Cmax we need to have samples at around Tmax, which was not available for all the subjects in PK analysis set. That is why there is a difference between Cmax calculated number of subjects vs number of subjects participated. | Cycle 2 day 1 | 
| Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to calculate AUC, we need to have enough PK samples collected to enable AUC estimation. That is why we have a difference in actual AUC calculated number of subjects vs number of subjects participated. | Cycle 2 day 1 | 
| Part A and B: Durvalumab Cmax After Single Dose at Cycle 1 Day 1 |  | Cycle 1 day 1 | 
| Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Ctrough we need to have samples at predose, which was not available for all the subjects in PK analysis set. That is why there is a difference between Ctrough calculated number of subjects vs number of subjects participated. | Cycle 4 day 1 | 
| Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Cmax we need to have samples at end of infusion, which was not available for all the subjects in PK analysis set. That is why there is a difference between Cmax calculated number of subjects vs number of subjects participated. | Cycle 8 day 1 | 
| Part A and B: Treme Cmax After Single Dose | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Cmax we need to have samples at end of infusion, which was not available for all the subjects in PK analysis set. That is why there is a difference between Cmax calculated number of subjects vs number of subjects participated. | Cycle 1 day 1 | 
| Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1 | If a subjects had at least one post dose PK sample they were part of PK analysis set. However, to estimate Ctrough we need to have samples at predose, which was not available for all the subjects in PK analysis set. That is why there is a difference between Ctrough calculated number of subjects vs number of subjects participated. | Cycle 4 day 1 | 
| Part A and B: Immunogenecity as Percent of ADA Positive Subjects | Subject was considered ADA positive if any post dose samples had ADA positive result. Result was not stratified based on post dose time points. | Throughout the study, up to 3.3 years | 
| Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | complete response, partial response, stable disease or progressive disease based on RECIST | assessed at every even numbered cycle with RECIST until disease progression, an average of 1 year | 
| Part B: Safety and Tolerability in Terms of Adverse Events | Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters | At every treatment and follow up visit until disease progression, an average of 1 year. | 
| Part B: Secondary Measures Change in Efficacy - Disease Control Rate | Disease control rate is confirmed complete response (CR), confirmed partial response (PR) and stable disease (SD) | Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months | 
| Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | Duration of overall response is according to RECIST 1.1 criteria measured from the time measurement criteria are first met for CR or PR, whichever is first recorded, until the first date that recurrent or PD is objectively documented (taking as reference for PD the smallest measurements recorded on study). DOR is only applied to treatment groups where at least one response patient was recorded. | Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 48 months | 
| Part B: Secondary Measures Change in Efficacy - PFS | progression-free survival (PFS): defined as the time from randomisation to the first documentation of PD as determined by the Investigator or death from any cause, whichever occurs first. Only includes progression events that occur within 126 days of the last evaluable assessment | Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months | 
| Part B: Secondary Measures Change in Efficacy - OS | overall survival (OS) - defined as the time from treatment allocation to death from any cause | Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 15 months | 
| Part B: Secondary Measures Change in Efficacy - OS at 12 Months | proportion of patients alive at 12 months: the percentage of patients surviving at 12 months after randomization to study drug | Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months | 
| Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | Percent STAT3 RNA change in expression level in peripheral blood in patients who had baseline (Screening or Day -7) sample for comparison. Data were only available for B1, B3, B5, B7 and B8. | At Cycle 2 Day 1 vs. Baseline | 
| Part B: Evaluation of PDL1 Expression | Tumors with PDL1-positive tumor cells at the designated cutoff. Data were only available for B1, B2, B3, B4, B7 and B8. | in baseline tumor samples | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma of the Head and Neck