Advanced Solid Tumors & Metastatic Squamous Cell Carcinoma of the Head and Neck
Conditions
Keywords
Carcinoma of the Head and Neck
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)
Interventions
Sponsors
AstraZeneca
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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: 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 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: 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 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 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: 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: 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 - 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: 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 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 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 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. |
| 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: 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: 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. |
Countries
Belgium, Germany, Italy, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORDr David Hong, MD
M.D. Anderson Cancer Center
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A1C1: AZD9150 2mg/kg + MEDI4736 20mg/kg 2mg/kg QW danvatirsen IV + 20mg/kg Q4W durvalumab | 4 |
| A1C2: AZD9150 3mg/kg + MEDI4736 20mg/kg 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab | 7 |
| A2C1: AZD5069 40mg BID + MEDI4736 20mg/kg 40mg BID AZD5069 (PO) + 20mg/kg Q4W durvalumab | 9 |
| A2C2: AZD5069 80mg BID + MEDI4736 20mg/kg 80mg BID AZD5069 (PO) + 20mg/kg Q4W durvalumab | 11 |
| A3C1: AZD5069 80mg BID + MEDI4736 20mg/kg 80 mg BID AZD5069 (PO) with scheduled dose holds and titrations + 20 mg/kg Q4W durvalumab | 15 |
| A4C1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab + 1 mg/kg Q4W tremelimumab | 9 |
| A4C2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme 2 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab + 1 mg/kg Q4W tremelimumab | 7 |
| A4C3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme 3 mg/kg Q2W danvatirsen IV + 20 mg/kg Q4W durvalumab + 1 mg/kg Q4W tremelimumab | 6 |
| A6C1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab | 14 |
| B1: AZD9150 3mg/kg + MEDI4736 20mg/kg Exp 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab | 24 |
| B2: AZD5069 40mg BID + MEDI4736 20mg/kg Exp 40 mg BID AZD5069 (PO) + 20 mg/kg Q4W durvalumab | 20 |
| B3: AZD9150 3mg/kg + MEDI4736 20mg/kg Naive 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab | 53 |
| B4: AZD5069 40mg BID + MEDI4736 20mg/kg Naive 40 mg BID AZD5069 (PO) + 20 mg/kg Q4W durvalumab | 22 |
| B5: AZD9150 3mg/kg 3 mg/kg QW danvatirsen IV | 14 |
| B6: AZD5069 40mg BID 40 mg BID AZD5069 (PO) | 10 |
| B6a: AZD5069 40mg BID Fed/Fasted AZD5069 40mg BID (PO): Fed/Fasted | 1 |
| B6b: AZD5069 40mg BID Fasted/Fed AZD5069 40mg BID (PO): Fasted/Fed | 1 |
| B7: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg 3 mg/kg QW danvatirsen IV + 20 mg/kg Q4W durvalumab | 55 |
| B8: AZD9150 400mg q2w + MEDI4736 1.5g Q4W 400 mg Q2W danvatirsen IV + 1.5 g Q4W durvalumab | 50 |
| Total | 332 |
Baseline characteristics
| Characteristic | A2C1: AZD5069 40mg BID + MEDI4736 20mg/kg | A2C2: AZD5069 80mg BID + MEDI4736 20mg/kg | A3C1: AZD5069 80mg BID + MEDI4736 20mg/kg | A4C1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | A4C2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | A4C3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | A6C1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | B1: AZD9150 3mg/kg + MEDI4736 20mg/kg Exp | B2: AZD5069 40mg BID + MEDI4736 20mg/kg Exp | B3: AZD9150 3mg/kg + MEDI4736 20mg/kg Naive | B4: AZD5069 40mg BID + MEDI4736 20mg/kg Naive | B6a: AZD5069 40mg BID Fed/Fasted | B5: AZD9150 3mg/kg | B6b: AZD5069 40mg BID Fasted/Fed | B7: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | B8: AZD9150 400mg q2w + MEDI4736 1.5g Q4W | Total | A1C1: AZD9150 2mg/kg + MEDI4736 20mg/kg | B6: AZD5069 40mg BID | A1C2: AZD9150 3mg/kg + MEDI4736 20mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.3 Years STANDARD_DEVIATION 9 | 64.5 Years STANDARD_DEVIATION 12.7 | 59.7 Years STANDARD_DEVIATION 10.2 | 53.4 Years STANDARD_DEVIATION 14.5 | 57.0 Years STANDARD_DEVIATION 15.8 | 54.0 Years STANDARD_DEVIATION 8.7 | 69.3 Years STANDARD_DEVIATION 8.2 | 65.5 Years STANDARD_DEVIATION 8.8 | 64.8 Years STANDARD_DEVIATION 9 | 61.5 Years STANDARD_DEVIATION 8.8 | 61.1 Years STANDARD_DEVIATION 7.7 | 64.0 Years | 60.6 Years STANDARD_DEVIATION 9.6 | 54.0 Years | 63.0 Years STANDARD_DEVIATION 11.6 | 62.3 Years STANDARD_DEVIATION 10.5 | 62.0 Years STANDARD_DEVIATION 10.3 | 55.8 Years STANDARD_DEVIATION 10.5 | 61.4 Years STANDARD_DEVIATION 9.2 | 64.1 Years STANDARD_DEVIATION 5.9 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 12 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or african american | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 10 Participants | 13 Participants | 8 Participants | 7 Participants | 5 Participants | 13 Participants | 22 Participants | 16 Participants | 51 Participants | 21 Participants | 1 Participants | 14 Participants | 1 Participants | 49 Participants | 45 Participants | 305 Participants | 4 Participants | 10 Participants | 7 Participants |
| Region of Enrollment Belgium | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 10 Participants | 4 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 4 Participants | 27 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Germany | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 4 Participants | 5 Participants | 24 Participants | 0 Participants | 4 Participants | 0 Participants |
| Region of Enrollment Great Britain | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 11 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 9 Participants | 13 Participants | 40 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Italy | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Spain | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 3 Participants | 12 Participants | 6 Participants | 0 Participants | 6 Participants | 0 Participants | 17 Participants | 10 Participants | 63 Participants | 0 Participants | 2 Participants | 0 Participants |
| Region of Enrollment United States | 9 Participants | 11 Participants | 15 Participants | 9 Participants | 7 Participants | 6 Participants | 14 Participants | 14 Participants | 14 Participants | 16 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 21 Participants | 18 Participants | 174 Participants | 4 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 7 Participants | 6 Participants | 4 Participants | 5 Participants | 0 Participants | 2 Participants | 1 Participants | 8 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 11 Participants | 7 Participants | 72 Participants | 2 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 8 Participants | 3 Participants | 3 Participants | 1 Participants | 14 Participants | 22 Participants | 19 Participants | 45 Participants | 17 Participants | 1 Participants | 14 Participants | 1 Participants | 44 Participants | 43 Participants | 260 Participants | 2 Participants | 6 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 3 / 7 | 5 / 9 | 6 / 11 | 9 / 15 | 8 / 9 | 6 / 7 | 1 / 6 | 7 / 14 | 21 / 24 | 18 / 20 | 41 / 53 | 16 / 22 | 11 / 14 | 9 / 10 | 1 / 1 | 1 / 1 | 35 / 55 | 22 / 50 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 9 / 9 | 10 / 11 | 15 / 15 | 9 / 9 | 7 / 7 | 5 / 6 | 14 / 14 | 22 / 24 | 19 / 20 | 51 / 53 | 20 / 22 | 14 / 14 | 10 / 10 | 1 / 1 | 1 / 1 | 55 / 55 | 48 / 50 |
| serious Total, serious adverse events | 0 / 4 | 1 / 7 | 3 / 9 | 5 / 11 | 5 / 15 | 5 / 9 | 2 / 7 | 2 / 6 | 3 / 14 | 10 / 24 | 7 / 20 | 30 / 53 | 9 / 22 | 9 / 14 | 6 / 10 | 1 / 1 | 0 / 1 | 28 / 55 | 21 / 50 |
Outcome results
Primary
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.
Time frame: 35 days
Population: All patients who were either assigned or randomized to study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 40 mg |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 80 mg |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 80 mg |
Primary
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.
Time frame: 35 days
Population: All patients who were either assigned or randomized to study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 2 mg/kg |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 3 mg/kg |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 3 mg/kg |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 2 mg/kg |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 3 mg/kg |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion | 3 mg/kg |
Primary
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
Time frame: At every treatment and follow up visit until disease progression, an average of 1 year.
Population: All patients who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Safety and Tolerability in Terms of Adverse Events | 4 Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Safety and Tolerability in Terms of Adverse Events | 7 Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Safety and Tolerability in Terms of Adverse Events | 9 Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Safety and Tolerability in Terms of Adverse Events | 10 Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Safety and Tolerability in Terms of Adverse Events | 15 Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Safety and Tolerability in Terms of Adverse Events | 9 Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Safety and Tolerability in Terms of Adverse Events | 7 Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Safety and Tolerability in Terms of Adverse Events | 5 Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Safety and Tolerability in Terms of Adverse Events | 14 Patients |
Primary
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.
Time frame: Assessed at every even-numbered cycles with RECIST until disease progression, up to 12 months.
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set. Only treatment groups with non-zero ORR are displayed here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 4.2 percentage of participants |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 10.0 percentage of participants |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 22.6 percentage of participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 4.5 percentage of participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 21.8 percentage of participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN. | 26.0 percentage of participants |
Secondary
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.
Time frame: Lead in day -7, AUC from time 0 to 12h post dose
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 AUC0-12h at Lead in Day -7 | 7028 nM.h/L | Geometric Coefficient of Variation 48.04 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 AUC0-12h at Lead in Day -7 | 17490 nM.h/L | Geometric Coefficient of Variation 37.71 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 AUC0-12h at Lead in Day -7 | 17810 nM.h/L | Geometric Coefficient of Variation 37.46 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 AUC0-12h at Lead in Day -7 | NA nM.h/L | — |
Secondary
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.
Time frame: Cycle 2 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | 7903 nM.h/L | Geometric Coefficient of Variation 56.98 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | 25500 nM.h/L | Geometric Coefficient of Variation 21.4 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | 22020 nM.h/L | Geometric Coefficient of Variation 37.13 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | NA nM.h/L | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | NA nM.h/L | — |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD5069 AUCss at Cycle 2 Day 1 | NA nM.h/L | — |
Secondary
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.
Time frame: Lead in day -7
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 Cmax at Lead in Day -7 | 1220 nM/L | Geometric Coefficient of Variation 45.38 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 Cmax at Lead in Day -7 | 3278 nM/L | Geometric Coefficient of Variation 46.17 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cmax at Lead in Day -7 | 3852 nM/L | Geometric Coefficient of Variation 45.13 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cmax at Lead in Day -7 | NA nM/L | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cmax at Lead in Day -7 | NA nM/L | — |
Secondary
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.
Time frame: Cycle 2 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | 1656 nM/L | Geometric Coefficient of Variation 48.79 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | 4195 nM/L | Geometric Coefficient of Variation 30.36 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | 4692 nM/L | Geometric Coefficient of Variation 29.12 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | NA nM/L | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | 3336 nM/L | Geometric Coefficient of Variation 23.34 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD5069 Cssmax at Cycle 2 Day 1 | NA nM/L | — |
Secondary
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.
Time frame: Cycle 2 day 1, AUC from time 0 to 6 h post dose
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | NA ng.h/ml | — |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | 61810 ng.h/ml | Geometric Coefficient of Variation 22.57 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | 53480 ng.h/ml | Geometric Coefficient of Variation 23.1 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | NA ng.h/ml | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | 44300 ng.h/ml | Geometric Coefficient of Variation 11.64 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | 51690 ng.h/ml | Geometric Coefficient of Variation 20.72 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | 62020 ng.h/ml | Geometric Coefficient of Variation 18.43 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1 | NA ng.h/ml | — |
Secondary
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.
Time frame: Lead in day -7, AUC from time 0 to 6h (post dose).
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 38860 ng.h/ml | Geometric Coefficient of Variation 17.31 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 60260 ng.h/ml | Geometric Coefficient of Variation 14.29 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 55960 ng.h/ml | Geometric Coefficient of Variation 14.72 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 36580 ng.h/ml | Geometric Coefficient of Variation 14.75 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 47080 ng.h/ml | Geometric Coefficient of Variation 13.1 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 57780 ng.h/ml | Geometric Coefficient of Variation 23.16 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | NA ng.h/ml | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | 54290 ng.h/ml | Geometric Coefficient of Variation 17.41 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | NA ng.h/ml | — |
| Part B7: AZD9150+MEDI4736: Naiive 1L | Part A and B: AZD9150 AUC0-6h at Lead in Day-7 | NA ng.h/ml | — |
Secondary
Part A and B: AZD9150 Cmax at Cycle 2 Day 1
Time frame: Cycle 2 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | NA ng/ml | — |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 30090 ng/ml | Geometric Coefficient of Variation 24.35 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 26870 ng/ml | Geometric Coefficient of Variation 26.66 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 14990 ng/ml | Geometric Coefficient of Variation 11.56 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 22100 ng/ml | Geometric Coefficient of Variation 18.12 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 23820 ng/ml | Geometric Coefficient of Variation 25.72 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 28030 ng/ml | Geometric Coefficient of Variation 10.75 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | NA ng/ml | — |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: AZD9150 Cmax at Cycle 2 Day 1 | 48540 ng/ml | Geometric Coefficient of Variation 26.87 |
Secondary
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.
Time frame: Lead in day -7
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Lead in Day -7 | 21800 ng/ml | Geometric Coefficient of Variation 16.76 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Lead in Day -7 | 30680 ng/ml | Geometric Coefficient of Variation 16.31 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Lead in Day -7 | 27570 ng/ml | Geometric Coefficient of Variation 13.21 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Lead in Day -7 | 18200 ng/ml | Geometric Coefficient of Variation 24.82 |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Lead in Day -7 | 23860 ng/ml | Geometric Coefficient of Variation 16.1 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Lead in Day -7 | 27230 ng/ml | Geometric Coefficient of Variation 21.54 |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Lead in Day -7 | NA ng/ml | — |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: AZD9150 Cmax at Lead in Day -7 | 23890 ng/ml | Geometric Coefficient of Variation 23.48 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: AZD9150 Cmax at Lead in Day -7 | NA ng/ml | — |
| Part B7: AZD9150+MEDI4736: Naiive 1L | Part A and B: AZD9150 Cmax at Lead in Day -7 | NA ng/ml | — |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: AZD9150 Cmax at Lead in Day -7 | 25430 ng/ml | Geometric Coefficient of Variation 30.23 |
Secondary
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.
Time frame: Cycle 8 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | NA ug/ml | — |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | NA ug/ml | — |
| Part B3: AZD9150+MED4736:Naiive 2L | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | NA ug/ml | — |
| Part B4:AZD5069+MEDI4736:Naiive Patients | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | NA ug/ml | — |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | 107.1 ug/ml | Geometric Coefficient of Variation 60.94 |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1 | 120.6 ug/ml | Geometric Coefficient of Variation 31.85 |
Secondary
Part A and B: Durvalumab Cmax After Single Dose at Cycle 1 Day 1
Time frame: Cycle 1 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: Durvalumab Cmax After Single Dose at Cycle 1 Day 1 | 499.3 ug/ml | Geometric Coefficient of Variation 32.28 |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Cmax After Single Dose at Cycle 1 Day 1 | 409.4 ug/ml | Geometric Coefficient of Variation 74.66 |
Secondary
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.
Time frame: Cycle 4 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1 | 100.6 ug/ml | Geometric Coefficient of Variation 52.48 |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1 | 148.7 ug/ml | Geometric Coefficient of Variation 22.38 |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1 | 107.1 ug/ml | Geometric Coefficient of Variation 60.94 |
| Part B8: AZD9150 (Every Other Week)+MEDI4736: Naive 1L | Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1 | 120.6 ug/ml | Geometric Coefficient of Variation 31.85 |
Secondary
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.
Time frame: Throughout the study, up to 3.3 years
Population: immunogenicity population, patient who provided at least one ADA samples for analysis.~Arms were combined together to help in data interpretation since there were not many ADA positive subjects in each to draw any useful conclusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: Immunogenecity as Percent of ADA Positive Subjects | 2.8 % of total analyzed patient |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: Immunogenecity as Percent of ADA Positive Subjects | 5 % of total analyzed patient |
Secondary
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.
Time frame: Cycle 1 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: Treme Cmax After Single Dose | 23840 ng/ml | Geometric Coefficient of Variation 23.39 |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: Treme Cmax After Single Dose | 20260 ng/ml | Geometric Coefficient of Variation 17.71 |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: Treme Cmax After Single Dose | 21290 ng/ml | Geometric Coefficient of Variation 20.67 |
Secondary
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.
Time frame: Cycle 4 day 1
Population: Pharmacokinetic population. PK parameters were estimated from PK evaluable subjects
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1 | NA ng/ml | — |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1 | NA ng/ml | — |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1 | 2999 ng/ml | Geometric Coefficient of Variation 9.78 |
Secondary
Part A: Antitumour Activity in Monotherapy and Combination Arms of Study
complete response, partial response, stable disease or progressive disease based on RECIST
Time frame: assessed at every even numbered cycle with RECIST until disease progression, an average of 1 year
Population: All patients who received at least 1 dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 1 Number of Patients |
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 2 Number of Patients |
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 1 Number of Patients |
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 3 Number of Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 3 Number of Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 1 Number of Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 6 Number of Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 1 Number of Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 0 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 5 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 1 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 4 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 0 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 3 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 0 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 9 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 2 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 1 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 6 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 2 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 0 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 5 Number of Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 2 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 1 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 1 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Complete response | 0 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Stable disease | 4 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Progression | 9 Number of Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part A: Antitumour Activity in Monotherapy and Combination Arms of Study | Partial response | 1 Number of Patients |
Secondary
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.
Time frame: At Cycle 2 Day 1 vs. Baseline
Population: Pharmacodynamics Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | -2.9 Percent |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | -9.8 Percent |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | -6.7 Percent |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | -22.9 Percent |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline | -27.1 Percent |
Secondary
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.
Time frame: in baseline tumor samples
Population: Patients with evaluable tumor samples
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 15 Participants |
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 8 Participants |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 12 Participants |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 4 Participants |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 27 Participants |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 12 Participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 15 Participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 5 Participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 27 Participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 8 Participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=1% in tumor cells | 21 Participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Evaluation of PDL1 Expression | Participants with PDL1 expression >=50% in tumor cells | 7 Participants |
Secondary
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
Time frame: At every treatment and follow up visit until disease progression, an average of 1 year.
Population: All patients who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Safety and Tolerability in Terms of Adverse Events | 22 Patients |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Safety and Tolerability in Terms of Adverse Events | 19 Patients |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Safety and Tolerability in Terms of Adverse Events | 51 Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Safety and Tolerability in Terms of Adverse Events | 20 Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Safety and Tolerability in Terms of Adverse Events | 14 Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Safety and Tolerability in Terms of Adverse Events | 10 Patients |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Safety and Tolerability in Terms of Adverse Events | 1 Patients |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Safety and Tolerability in Terms of Adverse Events | 1 Patients |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Safety and Tolerability in Terms of Adverse Events | 55 Patients |
| Part B7: AZD9150+MEDI4736: Naiive 1L | Part B: Safety and Tolerability in Terms of Adverse Events | 48 Patients |
Secondary
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)
Time frame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set. Only treatment groups with non-zero DCR are presented here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 20.8 Percentage of participants |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 20.0 Percentage of participants |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 37.7 Percentage of participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 18.2 Percentage of participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 28.6 Percentage of participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 32.7 Percentage of participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Disease Control Rate | 44.0 Percentage of participants |
Secondary
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.
Time frame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 48 months
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set. Only treatment groups with non-zero DoR are presented here.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 165.9 Weeks |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 29.0 Weeks |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 66.0 Weeks |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 37.0 Weeks |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 48.6 Weeks |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - Duration of Overall Response | 27.57 Weeks |
Secondary
Part B: Secondary Measures Change in Efficacy - OS
overall survival (OS) - defined as the time from treatment allocation to death from any cause
Time frame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 15 months
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS | 203.0 Days |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS | 288.0 Days |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS | 199.0 Days |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS | 254.0 Days |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS | 175.0 Days |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS | 451.0 Days |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS | 436.0 Days |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS | 318.0 Days |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS | 330.0 Days |
| Part B7: AZD9150+MEDI4736: Naiive 1L | Part B: Secondary Measures Change in Efficacy - OS | 353.0 Days |
Secondary
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
Time frame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set. Only treatment groups with non-zero OS at 12 months are presented here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 18.2 Percentage of participants |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 42.5 Percentage of participants |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 39.7 Percentage of participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 46.4 Percentage of participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 30.8 Percentage of participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 60.0 Percentage of participants |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 100.0 Percentage of participants |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 46.5 Percentage of participants |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - OS at 12 Months | 46.3 Percentage of participants |
Secondary
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
Time frame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
Population: All patients with unidimensional measurable disease at baseline as per the RECIST version 1.1 criteria who received at least 1 dose of study treatment barring except for important protocol deviation. Patients who have been manually assigned to treatment in Part B will be excluded from this analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A1 Cohort 1: AZD9150 2mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - PFS | 51.0 Days |
| Part A1 Cohort 2: AZD9150 3mg/kg + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - PFS | 51.0 Days |
| Part A4 Cohort 1: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - PFS | 66.5 Days |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - PFS | 52.00 Days |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - PFS | 47.0 Days |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - PFS | 41.5 Days |
| Part A4 Cohort 2: AZD9150 2mg/kg q1w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - PFS | 47.0 Days |
| Part A4 Cohort 3: AZD9150 3mg/kg q2w + MEDI4736 20mg/kg + Treme | Part B: Secondary Measures Change in Efficacy - PFS | 51.0 Days |
| Part A6: AZD9150 3mg/kg q1w + MEDI4736 20mg/kg | Part B: Secondary Measures Change in Efficacy - PFS | 85.0 Days |
| Part B7: AZD9150+MEDI4736: Naiive 1L | Part B: Secondary Measures Change in Efficacy - PFS | 104.0 Days |