Clinical trial NCT02499328: Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck
Official title: 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.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors & Metastatic Squamous Cell Carcinoma of the Head and Neck
Keywords: Carcinoma of the Head and Neck
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: MedImmune LLC
First posted: 2015-07-16
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

Eligibility 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 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.

Primary outcomes:
measure: Part A: Danvatirsen With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion
timeFrame: 35 days
measure: Part A: AZD5069 With Durvalumab MTDs (Maximum Tolerated Dose) or Recommended Doses for Dose-expansion
timeFrame: 35 days
measure: Part A: Safety and Tolerability in Terms of Adverse Events
timeFrame: At every treatment and follow up visit until disease progression, an average of 1 year.
measure: Part B: ORR (Objective Response Rate) in Patients With IL/2L RM-SCCHN.
timeFrame: Assessed at every even-numbered cycles with RECIST until disease progression, up to 12 months.
Secondary outcomes:
measure: Part A and B: AZD9150 AUC0-6h at Lead in Day-7
timeFrame: Lead in day -7, AUC from time 0 to 6h (post dose).
measure: Part A and B: AZD9150 Cmax at Lead in Day -7
timeFrame: Lead in day -7
measure: Part A and B: AZD9150 AUC0-6h at Cycle 2 Day 1
timeFrame: Cycle 2 day 1, AUC from time 0 to 6 h post dose
measure: Part A and B: AZD9150 Cmax at Cycle 2 Day 1
timeFrame: Cycle 2 day 1
measure: Part A and B: AZD5069 AUC0-12h at Lead in Day -7
timeFrame: Lead in day -7, AUC from time 0 to 12h post dose
measure: Part A and B: AZD5069 Cmax at Lead in Day -7
timeFrame: Lead in day -7
measure: Part A and B: AZD5069 Cssmax at Cycle 2 Day 1
timeFrame: Cycle 2 day 1
measure: Part A and B: AZD5069 AUCss at Cycle 2 Day 1
timeFrame: Cycle 2 day 1
measure: Part A and B: Durvalumab Cmax After Single Dose at Cycle 1 Day 1
timeFrame: Cycle 1 day 1
measure: Part A and B: Durvalumab Ctrough After Multiple Doses at Cycle 4 Day 1
timeFrame: Cycle 4 day 1
measure: Part A and B: Durvalumab Cmax After Multiple Doses at Cycle 8 Day 1
timeFrame: Cycle 8 day 1
measure: Part A and B: Treme Cmax After Single Dose
timeFrame: Cycle 1 day 1
measure: Part A and B: Treme Ctrough After Multiple Doses at Cycle 4 Day 1
timeFrame: Cycle 4 day 1
measure: Part A and B: Immunogenecity as Percent of ADA Positive Subjects
timeFrame: Throughout the study, up to 3.3 years
measure: Part A: Antitumour Activity in Monotherapy and Combination Arms of Study
timeFrame: assessed at every even numbered cycle with RECIST until disease progression, an average of 1 year
measure: Part B: Safety and Tolerability in Terms of Adverse Events
timeFrame: At every treatment and follow up visit until disease progression, an average of 1 year.
measure: Part B: Secondary Measures Change in Efficacy - Disease Control Rate
timeFrame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
measure: Part B: Secondary Measures Change in Efficacy - Duration of Overall Response
timeFrame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 48 months
measure: Part B: Secondary Measures Change in Efficacy - PFS
timeFrame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
measure: Part B: Secondary Measures Change in Efficacy - OS
timeFrame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 15 months
measure: Part B: Secondary Measures Change in Efficacy - OS at 12 Months
timeFrame: Assessed at every even-numbered cycles. Assessed at every even numbered cycle with RECIST until disease progression, up to 12 months
measure: Part B: Evaluation of AZD9150 Pharmacodynamics: Change in STAT3 RNA Level From Baseline
timeFrame: At Cycle 2 Day 1 vs. Baseline
measure: Part B: Evaluation of PDL1 Expression
timeFrame: in baseline tumor samples
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Duarte
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Orange
country: United States
facility: Research Site
state: California
city: San Francisco
country: United States
facility: Research Site
state: California
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Plantation
country: United States
facility: Research Site
state: Florida
city: Sarasota
country: United States
facility: Research Site
state: Florida
city: Lafayette
country: United States
facility: Research Site
state: Indiana
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Billings
country: United States
facility: Research Site
state: Montana
city: Morristown
country: United States
facility: Research Site
state: New Jersey
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Houston
country: United States
facility: Research Site
state: Texas
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Antwerpen
country: Belgium
facility: Research Site
city: Brussels
country: Belgium
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Namur
country: Belgium
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Frankfurt
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Hospitalet deLlobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Toledo
country: Spain
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Surrey
country: United Kingdom
facility: Research Site
city: Taunton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Dr David Hong, MD
role: PRINCIPAL_INVESTIGATOR
References: