Clinical Trials /

Study of Durvalumab (MEDI4736) After Chemo-Radiation for Microsatellite Stable Stage II-IV Rectal Cancer

NCT03102047

Description:

This study is being done to look at the safety and response to the investigational drug durvalumab (MEDI4736) following chemo-radiation therapy for patients with MSS stage II to IV rectal cancer. Durvalumab recognizes specific proteins on the surface of cancer cells and triggers the immune system to destroy the cancer cells. The chemoRT portion of the treatment will be completed just before the course of durvalumab is initiated. In order to learn more about certain characteristics of rectal cancer tumors, this study includes special research tests using samples from diagnostic tumors, a tissue sample from tumors removed during surgery, fresh tumor samples from an area where the cancer has recurred, and blood samples.

Related Conditions:
  • Rectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Durvalumab (MEDI4736) After Chemo-Radiation for Microsatellite Stable Stage II-IV Rectal Cancer
  • Official Title: A Phase II Study to Assess the Activity of PD-L1 Inhibition With Durvalumab (MEDI4736) After Chemo-Radiotherapy in Patients With Stage II-IV Microsatellite Stable (MSS) Rectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: NSABP FR-2
  • SECONDARY ID: ESR-15-11477
  • NCT ID: NCT03102047

Conditions

  • Rectal Cancer

Interventions

DrugSynonymsArms
durvalumabMEDI4736durvalumab

Purpose

This study is being done to look at the safety and response to the investigational drug durvalumab (MEDI4736) following chemo-radiation therapy for patients with MSS stage II to IV rectal cancer. Durvalumab recognizes specific proteins on the surface of cancer cells and triggers the immune system to destroy the cancer cells. The chemoRT portion of the treatment will be completed just before the course of durvalumab is initiated. In order to learn more about certain characteristics of rectal cancer tumors, this study includes special research tests using samples from diagnostic tumors, a tissue sample from tumors removed during surgery, fresh tumor samples from an area where the cancer has recurred, and blood samples.

Detailed Description

      The FR-2 study is designed as a phase II, open label, single arm study in patients with
      microsatellite stable (MSS) stages II-IV rectal cancer, to assess the activity of PD-L1
      inhibition with durvalumab (MEDI4736) monotherapy after standard chemo-radiotherapy
      (chemoRT). The study's primary aim is to determine the safety and efficacy of durvalumab
      immediately following chemoRT in patients undergoing subsequent surgery with stage II-IV
      rectal cancer.

      One dose of durvalumab will be given every 2 weeks for four total doses beginning within 3-7
      days of completing chemoRT. Surgery for all patients must occur within 8−12 weeks of the
      final dose of RT. Adjuvant chemotherapy after surgical recovery is at the discretion of the
      treating physician.

      During a safety run-in, the first 6 patients will be closely followed for 30 days after last
      dose of durvalumab without further accrual of patients. Patients will receive durvalumab
      (750mg IV infusion once every 2 weeks) for 4 total doses. No other concurrent anti-neoplastic
      medications or treatments aside from standard supportive care will be allowed during the
      durvalumab treatment phase.

      The safety run-in portion of the study will proceed to full enrollment at the proposed study
      therapy dose, (750 mg IV infusion every 2 weeks), if one or less dose-limiting toxicity (DLT)
      or significant safety concern attributable to durvalumab is identified during the observation
      period of the first 6 patients. If there are two or more DLTs, accrual to the study will stop
      with reassessment of the protocol.

      A total of 47 patients will be enrolled in this study for a sample size of 41 surgically
      evaluable patients.

      Required tissue and blood samples will be collected at specific time points and submitted for
      correlative science studies. Optional tumor and blood samples will be collected from
      consenting patients upon disease recurrence or progression.
    

Trial Arms

NameTypeDescriptionInterventions
durvalumabExperimentalIV infusion once every 2 weeks for 4 total doses
  • durvalumab

Eligibility Criteria

        Inclusion Criteria:

          -  The ECOG performance status must be 0 or 1

          -  Patients with biopsy-proven adenocarcinoma, stage II- IV rectal cancer.

          -  The tumor must have been determined to be mismatch repair proficient or microsatellite
             stable through CLIA approved testing (Immunohistochemistry [IHC], polymerase chain
             reaction [PCR], or Next-Generation Sequencing [NGS] assays).

          -  Patients must be candidates for planned surgical resection of their primary rectal
             cancer 8 - 12 weeks after completion of neoadjuvant chemoRT, even if stage IV.

          -  Planned neoadjuvant chemoRT treatment must conform to NCCN guidelines.

          -  Baseline staging prior to chemoRT initiation must be obtained. If stage IV, there must
             be documentation by PET/CT scan, CT scan, or MRI, that the patient has evidence of
             measurable distant disease per RECIST 1.1. Note: Patients with stage IV disease should
             have limited but measurable metastatic disease (one or two organs involved e.g., liver
             and lung) and primary tumor deemed resectable.

          -  Blood counts performed within 4 weeks prior to study entry must meet the following
             criteria:

               -  ANC must be greater than or equal to 1500/mm3

               -  Platelet count must be greater than or equal to 75,000/mm3; and

               -  Hemoglobin must be greater than or equal to 9 g/dL.

          -  Adequate hepatic function performed within 4 weeks prior to study entry must be met:

               -  Total bilirubin must be less than or equal to 1.5 x ULN (upper limit of normal)
                  for the lab unless the patient has a bilirubin elevation greater than 1.5 x Upper
                  limit of normal (ULN) to 3 x ULN due to Gilbert's disease or similar syndrome
                  involving slow conjugation of bilirubin; and

               -  AST and ALT must be less than or equal to 2.5 x ULN for the lab with the
                  following exception: for patients with documented liver metastases, AST and ALT
                  must be less than or equal to 5 x ULN.

          -  Adequate renal function within 4 weeks of study entry, defined as serum creatinine
             less than or equal to 1.5 x ULN for the lab. (If creatinine is 1.0-1.5 x ULN, the
             creatinine clearance should be greater than 40 mL/min per Cockcroft-Gault formula
             (Cockcroft-Gault 1976), or by 24-hour urine collection for determination of creatinine
             clearance.)

          -  Patients with reproductive potential (male/female) must agree to use accepted and
             highly effective methods of contraception while receiving durvalumab, and for at least
             3 months after the last dose of durvalumab.

          -  Female patients must either be of non-reproductive potential (i.e., post-menopausal by
             history: greater than or equal to 60 years old and no menses for greater than or equal
             to 1 year without an alternative medical cause; OR history of hysterectomy, OR history
             of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a
             negative serum pregnancy test upon study entry.

        Exclusion Criteria:

          -  Diagnosis of anal or small bowel carcinoma.

          -  Histopathology other than adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.

          -  Previous therapy with any PD1 or PD-L1 inhibitor (including durvalumab) for any
             malignancy.

          -  Completion of pelvic radiotherapy treatment for this current rectal cancer or any
             prior pelvic radiotherapy (e.g., prior prostate or cervical cancer therapy).

          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days after receiving the last dose of durvalumab.

          -  Acute or chronic hepatitis B or hepatitis C.

          -  Known history of human immunodeficiency virus (HIV) or acquired
             immunodeficiency-related (AIDS) illnesses.

          -  History of brain metastases, uncontrolled spinal cord compression, carcinomatous
             meningitis, or new evidence of brain or leptomeningeal disease.

          -  Active infection or chronic infection requiring chronic suppressive antibiotics.

          -  History of allogeneic organ transplantation.

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis).

          -  Active or prior history of autoimmune or inflammatory condition requiring ongoing
             immunosuppressive medications. This specifically includes use of immunosuppressive
             medication within 28 days before the first dose of durvalumab with the exceptions of
             intranasal corticosteroids or systemic corticosteroids at physiological doses, which
             do not exceed 10mg/day of prednisone or an equivalent corticosteroid.

          -  Any of the following cardiac conditions:

               -  Documented NYHA Class III or IV congestive heart failure

               -  Myocardial infarction within 6 months prior to study entry

               -  Unstable angina within 6 months prior to study entry

               -  Symptomatic arrhythmia

               -  Prolonged QTc greater than or equal to 470 ms. If QTc greater than or equal to
                  470ms, confirmation of eligible QTc requires mean calculation from 2 additional
                  electrocardiograms (ECGs) 2−5 minutes apart using Fridericia's Correction Formula
                  (mean less than 470 ms).

          -  Uncontrolled high blood pressure defined as systolic BP greater than or equal to 150
             mmHg or diastolic BP greater than or equal to 100 mmHg with or without
             anti-hypertensive medication. Patients with initial BP elevations are eligible if
             initiation or adjustment of BP medication lowers pressure to meet entry criteria.

          -  Ongoing or active gastritis or peptic ulcer disease.

          -  Active bleeding diatheses which in the opinion of the treating physician poses a
             significantly increased operative risk.

          -  Known history of previous diagnosis of tuberculosis.

          -  History of hypersensitivity to durvalumab or any excipient.

          -  Known history of active pneumonia, pneumonitis, symptomatic interstitial lung disease,
             or definitive evidence of interstitial lung disease described on CT scan, MRI, or
             chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous
             oxygen therapy.

          -  Other malignancies unless the patient is considered to be disease-free and has
             completed therapy for the malignancy greater than or equal to 12 months prior to study
             entry. Patients with the following cancers are eligible if diagnosed and treated
             within the past 12 months: carcinoma in situ of the cervix, colorectal carcinoma in
             situ, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

          -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
             investigator, would preclude the patient from meeting the study requirements, or
             interfere with interpretation of study results.

          -  Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be
             performed within 14 days prior to study entry according to institutional standards for
             women of childbearing potential.)

          -  Use of any investigational agent within 4 weeks prior to study entry.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Median Neoadjuvant Rectal (NAR) Score
Time Frame:From the beginning of the study to time of surgical resection, assessed over an estimated 12 weeks
Safety Issue:
Description:Compare Median Neoadjuvant Rectal (NAR) Score to historic control using the Wilcoxon test

Secondary Outcome Measures

Measure:Pathologic complete response rate to study therapy
Time Frame:At the time of surgical resection
Safety Issue:
Description:Pathologic Complete response rate ( pCR) (ypT0 and ypN0) of primary rectal cancer and regional nodes determined by pathological examination
Measure:Clinical complete response rate to study therapy
Time Frame:From one week prior to surgical resection up to time of surgical resection
Safety Issue:
Description:Clinical complete response rate cCR (ycT0) determined by the clinical absence of the primary tumor via digital rectal exam and proctoscopic exam
Measure:Rate of negative circumferential margin
Time Frame:At the time of surgical resection
Safety Issue:
Description:Rate of negative circumferential margin in surgical resection specimens
Measure:Sphincter function in patients with sphincter preserving surgery
Time Frame:From the time of surgical resection to 30 days after surgery
Safety Issue:
Description:Sphincter function as determined by number of adverse events related to bowel control
Measure:Severity of post-operative complications
Time Frame:From time of surgical resection to within 30 days post-operation
Safety Issue:
Description:Surgical complications that result in re-hospitalizations or death
Measure:Objective response rate to study therapy
Time Frame:From date of randomization through study therapy, generally 8-12 weeks
Safety Issue:
Description:Objective response rate (ORR) determined by RECIST 1.1 criteria
Measure:Duration of study therapy
Time Frame:From date study therapy begins to completion of study therapy, generally 8-12 weeks
Safety Issue:
Description:Duration of study therapy in selected patients
Measure:Frequency of adverse events assessed by CTCAE 4.0
Time Frame:From beginning of study therapy to 90 days after last dose of study therapy
Safety Issue:
Description:Frequency of adverse events categorized using the NCI Common Terminology Criteria for Adverse Events version 4.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NSABP Foundation Inc

Trial Keywords

  • microsatellite stable
  • MSS
  • durvalumab
  • NSABP

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