Submitted by: Ranelle Lou Dorado 2019-04-16 11:20:40 Last Updated by: Principe, Jeverly Ann S 2019-04-24 13:23:42 Export to PDF

A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With and following Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women With Locally Advanced Cervical Cancer 

PHRR190424-002106

D9100C00001

2019-CT0476

A Phase III, Randomized, Multi-Center, Double-Blind, Global Study to Determine the Efficacy and Safety of Durvalumab in Combination With and following Chemoradiotherapy Compared to Chemoradiotherapy Alone for Treatment in Women With Locally Advanced Cervical Cancer (CALLA)

This is a randomized, double-blind, placebo controlled, multi-center, global, Phase III study to determine the efficacy and safety of durvalumab when combined with SoC CCRT and administered as maintenance therapy following SoC CCRT compared to placebo with SoC
CCRT as systemic treatment in patients with FIGO Stages IB2 to IVA cervical cancer. In order to be eligible for this study, patients must be ≥18 years of age with FIGO Stages IB2 to IIB N+ and IIIA to IVA with any N. Patients must not have previously received any definitive surgical, radiation, or systemic therapy for cervical cancer and must be immunotherapy-naïve.

 

Approximately 714 patients from multiple sites will be randomized 1:1 to receive either durvalumab 1500 mg or placebo q4w for 24 doses. Patients in both arms will receive SoC CCRT consisting of EBRT + brachytherapy , and concurrent cisplatin 40 mg/m2 q1w × 5 weeks or carboplatin AUC 2 q1w × 5 weeks. A 6th week of platinum agent can be given per investigator discretion. Randomization will be stratified by disease stage status (FIGO Stage During Years 4, and 5, imaging/histopathologic assessments will be performed q24w and then annually until a PFS endpoint has been met or closure of the study.

 

The primary aim of this study is to assess the efficacy of durvalumab + SoC CCRT compared with placebo + SoC CCRT in terms of PFS, with a key secondary objective to assess the efficacy of durvalumab + SoC CCRT compared with placebo + SoC CCRT in terms of OS.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development

Ongoing

Institution Classification Region LTO #
AstraZeneca AB Private Business Sweden LTO-3000002234602
Institution Amount Region
AstraZeneca AB N/A Sweden
Name E-Mail Phone Number Postal Address
Mary Rose Chua MaryRose.Chua@astrazeneca.com +639998869154 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name E-Mail Phone Number Postal Address
Mary Rose Chua MaryRose.Chua@astrazeneca.com +639998869154 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippine
Name Expertise Affiliation
Warren Bacorro, MD Principal Investigator University of Santo Tomas Hospital
Teresa T. Sy Ortin, MD Principal Investigator Makati Medical Center
Kenneth Sy, MD Principal Investogator St. Luke's Medical Center - Quezon City
Raymond Sulay, MD Principal Investigator Perpetual Succour Hospital
Project Location Institutional Ethics Review Board
University of Santo Tomas Hospital University of Santo Tomas Hospital Institutional Review Board
Makati Medical Center Makati Medical Center Institutional Review Board
St. Luke's Medical Center - Quezon City St. Luke's Medical Center Institutional Ethics Review Committee
Perpetual Succour Hospital Perpetual Succour Hospital Institutional Ethics and Review Board

Women With Locally Advanced Cervical Cancer

  • PFS: Time from date of randomization until tumor progression or death due to any cause

  • OS: Time from date of randomization until the date of death by any cause
  • PFS in PD-L1 high patients:
  • ORR: The percentage of evaluable patients with a confirmed Investigator-assessed visit response of CR or PR
  • CR rate: Disappearance of all target and nontarget lesions as assessed at the 20 week assessment.
  • Incidence of Local Progession, Distant Disease Progression, and Secondary Malignancy: Number and percentage of patients who develop local progression, distant disease progression, or secondary malignancy
  • Change from baseline in EORTC QLQ-C30 and EORTC CX24
  • Blood concentration of durvalumab
  • Presence of ADAs for durvalumab

Recruiting

  • Canada
  • Japan
  • South Korea
  • United States

Clinical Trial

20181123094719

2019-03-26

None

Inclusion Criteria

Informed consent
1. Capability of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
2. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
3. Provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis

Age
4. Females age ≥18 years at the time of screening. For patients aged

Type of patient and disease characteristics
5. Histologically confirmed cervical adenocarcinoma, cervical squamous carcinoma, or cervical adenosquamous carcinoma and the following requirements:
 FIGO Stages IB2 to IIB, node positive (N≥1) -OR- FIGO Stages IIIA to IVA with any N stage (N≥0)
 Nodal staging may be either surgical or by imaging (RECIST v1.1)
 No evidence of metastatic disease (M0)

6. World Health Organization (WHO)/ECOG performance status (PS) of 0 or 1 atenrollment and randomization
7. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 TL at baseline. Tumor assessment by CT scan or MRI must be performed within 28 days prior to randomization.
8. Suitability and fitness for CCRT as determined by the Investigator
9. Adequate organ and marrow function as defined below:
 Hemoglobin ≥9.0 g/dL
 Absolute neutrophil count ≥1.5 × 109 /L
 Platelet count ≥75 × 109/L
 Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician and AstraZeneca.
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN
 Creatine clearance (CrCl) ≥60 mL/min calculated by Cockcroft-Gault equation (using actual body weight) or by measured 24-hour urine collection
Females:
Creatinine CL = Weight (kg) × (140 - Age) × 0.85
(mL/min) 72 × serum creatinine (mg/dL)
10. Life expectancy of at least 12 weeks

Weight
11. Body weight >30 kg
Sex
12. Female

Exclusion Criteria

Medical conditions
1. Diagnosis of small cell (neuroendocrine) histology cervical cancer
2. Intent to administer a fertility-sparing treatment regimen

3. Evidence of metastatic disease per RECIST 1.1 including lymph nodes ≥15 mm(short axis) above the L1 cephalad body or outside the planned radiation field.
4. Patients who have undergone a previous hysterectomy, including a supracervical hysterectomy, or will have a hysterectomy as part of their initial cervical cancer therapy
5. History of allogeneic organ transplantation
6. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
 Patients with vitiligo or alopecia
 Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
 Patients with any chronic skin condition that does not require systemic therapy
 Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician
 Patients with celiac disease controlled by diet alone
7. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
8. History of another primary malignancy except for
 Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
 Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
 Adequately treated carcinoma in situ without evidence of disease

9. History of active primary immunodeficiency
10. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV HBsAg result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
11. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry. Brain metastases will not be recorded as RECIST TLs at baseline.
12. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
13. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
14. Prior history of vesicovaginal, colovaginal, or rectovaginal fistula
Prior/concomitant therapy
15. Prior chemotherapy or radiation therapy for the management of cervical cancer
16. Exposure to immune-mediated therapy prior to the study for any indication including, but not limited to, other anti CTLA-4, anti-PD-1, anti-PD-L1, and anti- PD-L2 antibodies, or therapeutic anticancer vaccines
17. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
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 while receiving IP and up to 30 days after the last dose of IP
19. 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.
20. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

 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 premedication for hypersensitivity reactions (eg, CT scan premedication)


Prior/concurrent clinical study experience
21. Participation in another clinical study with an investigational product (IP) administered in the last 28 days
22. Previous IP assignment in the present study
23. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
24. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment

Other exclusions
25. Female patients who are pregnant or breastfeeding or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study treatment
26. 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
27. Genetics research study (optional):


Exclusion criteria for participation in the optional (DNA) genetics research component of the study include:
 Previous allogeneic bone marrow transplant
 Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection

Interventional

Durvalumab in combination with and following chemoradiotherapy

Durvalumab (MEDI4736, Imfinzi™) is a human monoclonal antibody (mAb) of the immunoglobulin G 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells. It is being developed by AstraZeneca/MedImmune for use in the treatment of cancer. The proposed mechanism of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD- 1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation of IFN-γ. In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell-dependent mechanism. Based on these data, durvalumab is expected to stimulate the patient’s anti-tumor immune response by binding to PD-L1 and shifting the balance toward an anti-tumor response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity and complementdependent cytotoxicity. To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either as monotherapy or in combination with other anticancer agents.

Randomized

Double Blind

Unspecified

Single

To assess the efficacy of durvalumab + SoC CCRT compared with placebo + SoC CCRT in terms of PFS

Phase III

10

Unspecified

Unspecified

01 Apr 2019

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