CTRI/2016/08/007169 [Registered on: 11/08/2016] Trial Registered Prospectively
Last Modified On:
28/04/2020
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Biological
Study Design
Randomized, Parallel Group Trial
Public Title of Study
A clinical trial to study the efficacy of MEDI4736 alone or in combination with Tremelimumab versus standard of care in Recurrent or Metastatic Head and Neck Cancer
Scientific Title of Study
A Phase III Randomized, Open-label, Multi-center, Global Study
of MEDI4736 Alone or in Combination with Tremelimumab versus
Standard of Care in the Treatment of First-line Recurrent or
Metastatic Squamous Cell Head and Neck Cancer Patients
AstraZeneca Pharma India Limited
Block N1, 12th floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road, Bangalore
Bangalore KARNATAKA 560045 India
Phone
008067748000
Fax
918067748857
Email
tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Tapankumar M Shah
Designation
Country Head - Site Management and Monitoring
Affiliation
AstraZeneca Pharma India Limited
Address
AstraZeneca Pharma India Limited
Block N1, 12th floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road, Bangalore
Bangalore KARNATAKA 560045 India
Phone
008067748000
Fax
Email
tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Södertälje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
Austria Belgium Brazil Canada France Germany Greece India Italy Japan Philippines Poland Portugal Republic of Korea Romania Russian Federation Slovakia Spain Taiwan Thailand Ukraine United Kingdom United States of America Viet Nam
2. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the United States, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.(For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.)
3. Histologically or cytologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to local curative therapy with surgery or radiation therapy.
4. No prior systemic therapy for recurrent/metastatic disease.Systemic therapy given as part of multimodality treatment for locally advanced or locally recurrent disease is allowed.
5. Able and willing to give valid written consent to provide newly acquired tumor tissue (preferred) or archival tissue (<3 years old) for the purpose of establishing PD-L1 status. Tumor lesions used for newly acquired biopsies should not be the same lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.
6. For patients with OPC only: known HPV status prior to randomization.
7. Confirmed PD-L1–positive or –negative SCCHN by the Ventana SP263 IHC assay
- On newly acquired tumor tissue (preferred) or archival tissue (<3 years old)
- If the patient’s PD-L1 status has already been assessed using the analytically validated Ventana assay as a part of the screening process for another AstraZeneca/MedImmune study, this test result can be used for the determination of eligibility.
- Note: A positive PD-L1 sample is measured using a defined cut-off based on ≥25% of tumor cells with membrane staining of any intensity for PD-L1. A negative PD-L1 sample is determined by 0% to 24% of tumor cells with membrane staining for PD L1.
8. World Health Organization (WHO)/ECOG performance status of 0 or 1
9. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions in a previously irradiated field can be used as measurable disease provided that there has been demonstrated progression in the lesion and the lesion measures at least 20 mm.
10. Patients must have no prior exposure to immune-mediated therapy, including anti CTLA-4, anti PD-1, anti–PD-L1, or anti–programmed cell death ligand 2 antibodies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor.
11. Adequate organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening, defined as follows:
- Hemoglobin ≥9 g/dL
- Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L)
- Platelet count ≥100000/mm3 (100 × 109/L)
- Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
- ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
- Calculated creatinine clearance >40 mL/min as determined by Cockcroft-Gault (using actual body weight) (creatinine clearance of 60 mL/min is needed if cisplatin is used)
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
- Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments or if they have luteinizing hormone and follicle-stimulating hormone levels in the post menopausal range for the institution.
- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution, or had radiation-induced oophorectomy with last menses >1 year ago, or had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
ExclusionCriteria
Details
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1. Histologically or cytologically confirmed head and neck cancer of any other primary anatomic location in the head and neck not specified in the inclusion criteria including patients with SCCHN of unknown primary or non-squamous histologies (eg, nasopharynx or salivary gland)
2. Tumor progression or recurrence within 6 months of last dose of platinum therapy given as part of multimodality treatment for locally advanced or locally recurrent disease.
3. Receipt of any radiotherapy or hormonal therapy for cancer treatment within 30 days prior to first dose of study treatment.
4. Receipt of last dose of an approved (marketed) anticancer therapy (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the first dose of study treatment. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Investigator.
5. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment.
6. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
7. Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia, and the laboratory values defined in the inclusion criterion
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician.
- Patients with a toxicity not reasonably expected to be exacerbated by treatment with their assigned IP (eg, hearing loss, gastrostomy tube) may be included after consultation with the Study Physician.
8. Current or prior use of immunosuppressive medication within 14 days before the first dose of their assigned IP. The following are exceptions to this criterion unless otherwise indicated:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
- Steroids as pre-medication for hypersensitivity reactions (eg, CT scan pre medication) and/or as anti-emetics for the SoC arm
9. History of allogeneic organ transplantation
10. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment
11. Uncontrolled intercurrent illness, including, but not limited to ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs from IP, or compromise the ability of the patient to give written informed consent
12. History of another primary malignancy within the last 5 years except for the following:
- Non-invasive malignancies, such as cervical carcinoma in situ or non-melanomatous carcinoma of the skin that has been surgically cured. Other in situ carcinomas that have been adequately treated may be permitted after detailed discussion with the Sponsor.
13. Patients with a history of brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs
14. Mean QT interval corrected for heart rate ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia’s Correction
15. History of active primary immunodeficiency
16. Active tuberculosis
17. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IP.
19. Female patients of childbearing potential who are pregnant or breast-feeding or who are not willing to employ a highly effective method of birth control from screening to 90 days after the last dose of MEDI4736 monotherapy or 180 days after the last dose of MEDI4736 + tremelimumab combination therapy and non-sterilized male patients who are sexually active with a female partner of childbearing potential who are not willing to employ male condom plus spermicide from screening to 90 days after the last dose of MEDI4736 monotherapy or 180 days after the last dose of MEDI4736 + tremelimumab combination therapy. For patients randomized to receive SoC treatment, follow the local prescribing information relating to contraception, the time limit for such precautions, and any additional restrictions for agents in the SoC treatment regimen.
20. Known allergy or hypersensitivity to IP or any IP excipient
21. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the IP or interpretation of patient safety or study results
22. For patients randomized to the SoC arm, any contraindication to a specific SoC agent as specified by the accompanying package insert or Summary of Product Characteristics
23. Patient weight of <30 kg
24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/MedImmune staff and/or staff at the study site)
To further assess the efficacy of MEDI4736 PLUS tremelimumab combination therapy compared to SoC in terms of OS, PFS, ORR, DoR, BoR, TFST, TSST, APF6, APF12, PFS2, OS12, OS18 and OS24
- OS, OS12, OS18, OS24
- PFS, ORR, APF6 and APF12 using investigator assessments according to RECIST 1.1
- DoR and BoR
- PFS2
- TFST and TSST
To assess the efficacy of MEDI4736 monotherapy compared to SoC in terms of PFS, ORR, DoR, BoR, TFST, TSST, APF6, APF12, PFS2, OS, OS12, OS18 and OS24
- Noninferiority in OS
- OS
- OS12, OS18, OS24
- PFS, ORR, APF6 and APF12 using investigator assessments according to RECIST 1.1
- DoR and BoR
- PFS2
- TFST and TSST
To assess the efficacy of MEDI4736 PLUS tremelimumab combination therapy compared to MEDI4736 monotherapy in terms of PFS, ORR, and OS to MEDI4736 monotherapy in terms of Progression-free survival(PFS), Objective Response Rate (ORR), and Overall Survival (OS)
- PFS and ORR
- OS
To assess the efficacy of MEDI4736 PLUS OR MINUS tremelimumab compared to SoC in terms of PFS, ORR, OS, OS12, OS18, OS24, APF6 and APF12
OS, PFS, ORR, OS12, OS18, OS24, APF6 and APF12
To assess disease-related symptoms and health-related quality of life in patients treated with MEDI4736 PLUS tremelimumab combination therapy and MEDI4736 monotherapy compared to SoC using the European Organisation for Research and Treatment of Cancer (EORTC) 30-item Core Quality of Life Questionnaire (QLQ-C30) version 3 and the 35-item Head and Neck Quality of Life Questionnaire (QLQ H&N35) module
- EORTC QLcQ-C30
- EORTC QLQ-H&N35
- Changes in ECOG
To assess the PK of MEDI4736 PLUS tremelimumab combination therapy and MEDI4736 monotherapy
- Concentration of MEDI4736 and tremelimumab in blood and PK parameters
To investigate the immunogenicity of MEDI4736 and tremelimumab
Total Sample Size="760" Sample Size from India="23" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
This is a randomized, open-label, multi-center, 3-arm, global Phase III study to determine the efficacy and safety of MEDI4736 + tremelimumab combination or MEDI4736 monotherapy versus SoC (EXTREME regimen) in the treatment of patients with SCCHN who have not received prior systemic chemotherapy for recurrent or metastatic disease. Patients will be randomized in a 2:1:1 ratio to MEDI4736 + tremelimumab combination therapy, MEDI4736 monotherapy, or SoC. Patients in all arms will continue therapy until progression. Tumor assessments will be performed on computed tomography scans or magnetic resonance imaging scans, preferably with intravenous (IV) contrast. Efficacy for all patients will be assessed by objective tumor assessments every 6 weeks for the first 24 weeks, then every 8 weeks thereafter until treatment discontinuation due to progression or toxicity. All patients will be followed every 3 months for survival after progression is confirmed.