| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Part A (US ONLY): advanced solid malignancies
Part B (NA, EU): Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck |
|
| E.1.1.1 | Medical condition in easily understood language |
Part A (US ONLY): advanced solid tumor
Part B (NA, EU): Recurrent and/or spreading tumor of Head and Neck |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A (dose escalation-US ONLY)
To determine the MTDs or recommended doses for dose-expansion and to determine the safety profiles of either AZD9150 or AZD5069 in combination with MEDI4736 and/or MEDI4736/tremelimumab (treme) in patients with advanced solid malignancies refractory to standard therapy or for which no standard of care regimen currently exists.
|
Part B (dose expansion-NA, EU)
to evaluate the ORR of AZD9150 and AZD5069 both as monotherapy and in combination with MEDI4736 in the second-line treatment of patients with RM-SCCHN and in patients with no prior exposure to anti-PD-(L)1 therapies and also in who have not received prior systemic treatment for recurrent or metastatic SCCHN (1L RM SCCHN).
To evaluate ORR of AZD9150 as fixed doses Q2W in patients with no prior exposure to anti-PD-(L)1 therapies and who have not received prior systemic treatment for recurrent or metastatic SCCHN (1M RM SCCHN).
To evaluate ORR of AZD9150 as fixed dosed Q2W in patients with no prior exposure to anti-PD-(L)1 therapies and who have not received prior systemic treatment for recurrent or metastatic SCCHN (1L RM SCCHN). |
|
| E.2.2 | Secondary objectives of the trial |
Part A: To assess: Pharmacokinetics (PK):AZD9150, AZD5069 & MEDI4736, treme, immunogenicity (IM):MEDI4736 or MEDI4736/treme with AZD9150 or AZD5069, AZD9150 with MEDI4736, blood pharmacodynamic (PD) response:AZD9150 & MEDI4736, baseline circulating myeloid-derived suppressor cells (MDSC) & effect of treatment on them, anti-tumor activity of AZD9150 or AZD5069 with MEDI4736 and/or MEDI4736/treme
Part B: To assess: safety & tolerability of AZD9150 & AZD5069 alone & with MEDI4736, secondary efficacy measures (disease control rate; overall response duration; progression-free survival; overall survival; proportion of patients alive at 12 months), PK:AZD9150 & AZD5069 alone & with MEDI4736, urinary PK of AZD9150, PK of MEDI4736 with AZD9150 or AZD5069, IM: MEDI4736 with AZD9150 or AZD5069, IM of AZD9150 alone or with MEDI4736, blood PD response for AZD9150 & MEDI4736, tumor cell PD, baseline circulating MDSC and effect of treatment on them, baseline tumor PD-L1 expression
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Eastern Cooperative Oncology Group performance status score of 0 or 1
-Measurable disease
-Male and female above 18 years
- Undergone 1-3 previous regimens (B1-B6) of cytoreductive therapies including, but not limited to, platinum-based compounds, taxanes, or 5-fluorouracil. For patients in Arm B7 & B8 no prior systemic treatment should have been received for RM SCCHN.
-Adequate organ and marrow function
-Women of childbearing potential and men who are sexually active with a female partner of childbearing potential must prevent pregnancy and women may not be breast feeding
Additional inclusion criteria for Part A:
-Histological confirmation of a solid malignancy (other than HCC) refractory to standard therapy or for which no standard of care regimen currently exists.
Additional inclusion criteria Arm A6 of Part A
-Has a histological confirmation of castrate-resistant prostate cancer.
Additional inclusion criteria for Part B:
-Histologically and/or cytologically confirmed SCCHN that is RM and not amenable 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 be medically fit and willing to undergo a biopsy during screening and, unless clinically contraindicated, at the end of Cycle 1.
-Must have failed for least 1 prior platinum-based chemotherapy for RM-SCCHN (B1-B6).
-Must have received no prior systemic therapy for RM SCCHN (B7 & B8).
Additional inclusion criteria for Part B, arms B1 & B2
Has had prior exposure to any anti PD (L)1 antibody
|
|
| E.4 | Principal exclusion criteria |
-Symptomatic spinal cord compression
-Second malignancy
-Concurrent chemotherapy, radiotherapy, immunotherapy, or biologic or hormonal therapy for cancer
-Ongoing toxicity related to prior treatment and assessed as grade >1 Immune-related adverse events (AEs) while receiving prior immunotherapy (including anti-cytoxic T-lymphocyte-associated protein 4 treatment) and assessed as grade ≥3
-Has active or prior documented autoimmune disease within the past 2 years with the exception of vitiligo, Grave’s disease, and/or psoriasis not requiring systemic treatment
-Active or prior documented inflammatory bowel disease
-History of primary immunodeficiency
-Prior organ transplant that requires use of immunosuppressive treatment
-Cardiac conditions that render the patient unsuitable for participation in the study
-Inability to take oral medications and/or has a clinical or radiological diagnosis of bowel obstruction
-History of allergic reactions attributed to the study treatments (AZD9150, AZD5069, or MEDI4736 or treme (Part A)), their compounds, or agents of similar chemical or biologic composition
-Suffers from a comorbidity that in the opinion of the Investigator renders the patient unsuitable for participation in the study
-As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases such as active bleeding diatheses, or is positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV)
-History of tuberculosis
-Condition that, in the opinion of the Investigator, would interfere with the evaluation of the study drugs or the interpretation of patient safety or study results
-Live attenuated vaccine within 28 days before the first dose of study drug
-Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
-Patients with brain metastases considered stable may be enrolled into Part A of the study; they are excluded form Part B of the study
-Patients must not be included in the optional genetic research if they have previously received an allogeneic bone marrow transplant or have received non-leukocyte depleted whole blood transfusion(s) within 120 days before the date of the genetic sample collection
Additional exclusion criteria for Part A:
-Patients with clinically active brain metastases (known or suspected) are excluded
unless the brain metastases have been previously treated and are considered stable.
Stable brain metastases are defined as no change on CT scan or magnetic resonance
imaging (MRI) scan for a minimum of 2 months AND no change in steroid dose for
a minimum of 4 weeks, unless change due to intercurrent infection or other acute
event.
- Has had prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody.
Additional exclusion criteria for Part B:
Patients with brain metastases (known or suspected) are excluded
Additional exclusion criteria Part B: treatment arms B3, B4, B5, B6 and B7 and B8.
Has had prior exposure to AZD9150, AZD5069, MEDI4736, or any other anti PD (L)1 antibody.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
-MTD or recommended dose for dose expansion
-AEs, SAEs, laboratory evaluations, vital signs, and physical examinations
-Treatment-emergent AEs (TEAEs), SAEs and death(s), graded in accordance with NCI CTCAE v4.03
Part B
-Objective response - defined as a CR or PR according to RECIST version 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
-MTD or recommended dose for dose expansion: based on patients completing DLT evaluation period as defined in protocol for each arm.
- Patients are to be followed up for 28 (+7) days after the last dose of study treatment for any new reports of AEs, SAEs. Safety follow-up for IM will continue for all patients treated with MEDI4736 for 90 days after the last dose of MEDI4736 or until the initiation of subsequent anticancer therapy.
Part B:
Tumour assessments to be performed using RECIST 1.1 at screening, Day 15 of Cycle 2, beginning of each subsequent even numbered cycle, and at end of treatment visit. Patients discontuning treatment for reasons other than progressive disease (PD) will continue to undergo assessment every 2 months until PD is noted.
|
|
| E.5.2 | Secondary end point(s) |
Part A & B:
Tumor response by RECIST, Pharmacokinetics (ADAs, STAT3 knockdown Tumor PDL1 expression) safety.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Response- Scr, C2D15, every 8 weeks until PD. OS: from C1D1 until death. AEs- Scr, all clinic visits until 28 days after the last dose. PK (blood)- AZD9150 & AZD5069: lead in, C1D1, C2D1 & Day 1 of all cycles (B8: D1 of C1, 2, 3, 5, 6, 9, 11 and every 6 cycles). MEDI4736: C1D1, C2D15, Cycle 4 & all even cycles. 90 days after last dose of MEDI4736 for patients stopping drug. IM for MEDI4736 & AZD9150: C1D1, Cycle 2, & Day 1 of even-numbered cycle & 90 days after last dose of MEDI4736 for patients stopping drug. |
PD (blood): Scr, Day -7; C1D1&8; D1 of all subsequent cycles & EOT. sPD-L1 protein: C1D1; C2D15; & Day 1 of even cycles & 90 days after last dose of MEDI4736 for patients stopping drug (All cohorts except B8). MDSC1&2: Scr, Day -7, C1, 2, 3, 5 D1 & EOT (All cohorts except B7 or B8). Tumor STAT3: Baseline & on-treatment biopsies.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 15 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial will end when all patients have been successfully followed up for survival endpoint with the exception of patients who withdraw and go on alternate anti cancer therapy or patients who are lost to follow up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
Print
