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.
Overview
- Phase
- Phase 1
- Intervention
- MEDI4736
- Conditions
- Advanced Solid Tumors & Metastatic Squamous Cell Carcinoma of the Head and Neck
- Sponsor
- AstraZeneca
- Enrollment
- 340
- Locations
- 45
- Primary Endpoint
- Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion
- Status
- Completed
- Last Updated
- 2 months ago
Overview
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)
Investigators
Eligibility Criteria
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
- •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
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.
Arms & Interventions
Part A2: AZD5069 / MEDI4736
Patients allocated in cohort of arm A2 (AZD5069/MEDI4736 will be evaluated for DLT until an MTD is achieved.
Intervention: MEDI4736
Part A1: AZD9150 / MEDI4736
Patients allocated in cohort of arm A1 (AZD9150/MEDI4736 will be evaluated for DLT until an MTD is achieved.
Intervention: AZD9150
Part A1: AZD9150 / MEDI4736
Patients allocated in cohort of arm A1 (AZD9150/MEDI4736 will be evaluated for DLT until an MTD is achieved.
Intervention: MEDI4736
Part A2: AZD5069 / MEDI4736
Patients allocated in cohort of arm A2 (AZD5069/MEDI4736 will be evaluated for DLT until an MTD is achieved.
Intervention: AZD5069
Part B1:AZD9150+MEDI4736:PDL1 pretreated
Patients in arm B1 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: AZD9150
Part B1:AZD9150+MEDI4736:PDL1 pretreated
Patients in arm B1 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: MEDI4736
Part B2:AZD5069+MEDI4736:PDL1 pretreated
Patients in arm B2 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: MEDI4736
Part B2:AZD5069+MEDI4736:PDL1 pretreated
Patients in arm B2 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: AZD5069
Part B3: AZD9150+MED4736:naiive 2L
Patients in arm B3 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: AZD9150
Part B3: AZD9150+MED4736:naiive 2L
Patients in arm B3 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: MEDI4736
Part B4:AZD5069+MEDI4736:naiive patients
Patients in arm B4 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: MEDI4736
Part B4:AZD5069+MEDI4736:naiive patients
Patients in arm B4 will be evaluated for efficacy until disease progression and then followed-up for safety and survival.
Intervention: AZD5069
Part B5: AZD9150 in naiive patients
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
Intervention: AZD9150
Part B6:AZD5069 in naiive patients
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
Intervention: AZD5069
Part A3: AZD5069/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
Intervention: MEDI4736
Part A3: AZD5069/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
Intervention: AZD5069
Part A4: AZD9150/Treme/MEDI4736
Patients allocated in cohort of arm A4 (AZD9150/treme/MEDI4736) will be evaluated for DLT and MTD
Intervention: AZD9150
Part A4: AZD9150/Treme/MEDI4736
Patients allocated in cohort of arm A4 (AZD9150/treme/MEDI4736) will be evaluated for DLT and MTD
Intervention: MEDI4736
Part A4: AZD9150/Treme/MEDI4736
Patients allocated in cohort of arm A4 (AZD9150/treme/MEDI4736) will be evaluated for DLT and MTD
Intervention: tremelimumab (treme)
Part A5: AZD5069/Treme/MEDI4736
Patients allocated in cohort of arm A5 (AZD5069/treme/MEDI4736) will be evaluated for DLT and MTD.
Intervention: MEDI4736
Part A5: AZD5069/Treme/MEDI4736
Patients allocated in cohort of arm A5 (AZD5069/treme/MEDI4736) will be evaluated for DLT and MTD.
Intervention: AZD5069
Part A5: AZD5069/Treme/MEDI4736
Patients allocated in cohort of arm A5 (AZD5069/treme/MEDI4736) will be evaluated for DLT and MTD.
Intervention: tremelimumab (treme)
Part A6: AZD9150/MEDI4736
Patients allocated in cohort of arm A6 (AZD9150/MEDI4736) will be evaluated for safety, PK and PD.
Intervention: AZD9150
Part A6: AZD9150/MEDI4736
Patients allocated in cohort of arm A6 (AZD9150/MEDI4736) will be evaluated for safety, PK and PD.
Intervention: MEDI4736
Part A7: AZD5069/MEDI4736
Patients allocated in cohort of arm A7 (AZD5069/MEDI4736) will be evaluated for safety, PK and PD.
Intervention: MEDI4736
Part A7: AZD5069/MEDI4736
Patients allocated in cohort of arm A7 (AZD5069/MEDI4736) will be evaluated for safety, PK and PD.
Intervention: AZD5069
Part B7: AZD9150+MEDI4736: naiive 1L
Patients in Arm B7 will be evaluated for efficacy until disease progression and then followed up for safety and survival
Intervention: AZD9150
Part B7: AZD9150+MEDI4736: naiive 1L
Patients in Arm B7 will be evaluated for efficacy until disease progression and then followed up for safety and survival
Intervention: MEDI4736
Part B8: AZD9150 (every other week)+MEDI4736: naive 1L
Patients in Arm B8 will be evaluated for efficacy until disease progression and then followed up for safety and survival
Intervention: AZD9150
Part B8: AZD9150 (every other week)+MEDI4736: naive 1L
Patients in Arm B8 will be evaluated for efficacy until disease progression and then followed up for safety and survival
Intervention: MEDI4736
Outcomes
Primary Outcomes
Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion
Time Frame: 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
Time Frame: 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
Time Frame: 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.
Time Frame: 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 Outcomes
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Part A and B: AZD5069 AUC0-12h at Lead in Day -7(Lead in day -7, AUC from time 0 to 12h post dose)
- Part A and B: AZD9150 Cmax at Lead in Day -7(Lead in day -7)
- Part A and B: AZD5069 Cmax at Lead in Day -7(Lead in day -7)
- Part A and B: AZD5069 Cssmax at Cycle 2 Day 1(Cycle 2 day 1)
- Part A and B: AZD5069 AUCss at Cycle 2 Day 1(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(Cycle 4 day 1)
- Part A and B: Treme Cmax After Single Dose(Cycle 1 day 1)
- Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1(Cycle 4 day 1)
- 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.)
- Part A and B: AZD9150 AUC0-6h at Lead in Day-7(Lead in day -7, AUC from time 0 to 6h (post dose).)
- Part A and B: Immunogenecity as Percent of ADA Positive Subjects(Throughout the study, up to 3.3 years)
- 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)
- 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)
- Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline(At Cycle 2 Day 1 vs. Baseline)
- Part B: Evaluation of PDL1 Expression(in baseline tumor samples)