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

Phase 1

Active, not recruiting

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

Interventions: Drug: AZD9150
Drug: MEDI4736
Drug: AZD5069
Drug: tremelimumab (treme)

Registration Number: NCT02499328

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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)

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 340

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion	35 days	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.
Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion	35 days	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.
Part A: Safety and Tolerability in Terms of Adverse Events	At every treatment and follow up visit until disease progression, an average of 1 year.	Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters
Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN.	Assessed at every even-numbered cycles with RECIST until disease progression, up to 12 months.	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.

Secondary Outcome Measures

Name	Time	Method
Part A and B: AZD9150 Cmax at Cycle 2 Day 1	Cycle 2 day 1
Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1	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.
Part B: Secondary Measures Change in Efficacy - Disease Control Rate	Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months	Disease control rate is confirmed complete response (CR), confirmed partial response (PR) and stable disease (SD)
Part B: Secondary Measures Change in Efficacy - Duration of Overall Response	Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 48 months	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.
Part B: Secondary Measures Change in Efficacy - OS	Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 15 months	overall survival (OS) - defined as the time from treatment allocation to death from any cause
Part B: Secondary Measures Change in Efficacy - OS at 12 Months	Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months	proportion of patients alive at 12 months: the percentage of patients surviving at 12 months after randomization to study drug
Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1	Cycle 2 day 1, AUC from time 0 to 6 h post dose	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.
Part A and B: AZD5069 AUC0-12h at Lead in Day -7	Lead in day -7, AUC from time 0 to 12h post dose	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.
Part A and B: AZD9150 Cmax at Lead in Day -7	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.
Part A and B: AZD5069 Cmax at Lead in Day -7	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.
Part A and B: AZD5069 Cssmax at Cycle 2 Day 1	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.
Part A and B: AZD5069 AUCss at Cycle 2 Day 1	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.
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	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.
Part A and B: Treme Cmax After Single Dose	Cycle 1 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.
Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1	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.
Part B: Safety and Tolerability in Terms of Adverse Events	At every treatment and follow up visit until disease progression, an average of 1 year.	Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters
Part A and B: AZD9150 AUC0-6h at Lead in Day-7	Lead in day -7, AUC from time 0 to 6h (post dose).	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.
Part A and B: Immunogenecity as Percent of ADA Positive Subjects	Throughout the study, up to 3.3 years	Subject was considered ADA positive if any post dose samples had ADA positive result. Result was not stratified based on post dose time points.
Part A: Antitumour Activity in Monotherapy and Combination Arms of Study	assessed at every even numbered cycle with RECIST until disease progression, an average of 1 year	complete response, partial response, stable disease or progressive disease based on RECIST
Part B: Secondary Measures Change in Efficacy - PFS	Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months	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
Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline	At Cycle 2 Day 1 vs. 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.
Part B: Evaluation of PDL1 Expression	in baseline tumor samples	Tumors with PDL1-positive tumor cells at the designated cutoff. Data were only available for B1, B2, B3, B4, B7 and B8.