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
Overview
- Phase
- Phase 2
- Intervention
- durvalumab
- Conditions
- Rectal Cancer
- Sponsor
- NSABP Foundation Inc
- Enrollment
- 45
- Locations
- 43
- Primary Endpoint
- Median modified Neoadjuvant Rectal (mNAR) Score
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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 44 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. Given the increasing use of non-operative therapy for patients with rectal cancer who achieve a complete clinical response and in order to maximize the inclusion of patients participating in this trial, the primary endpoint was changed from NAR score to modified NAR score (mNAR). The mNAR score substitutes values from clinical staging for the pathologic T-Stage and N-Stage for those patients who don't go to surgery because of a complete clinical response and consequently have no pathology. Additionally, because of enrollment challenges related to COVID-19 pandemic and the exploratory nature of including stage IV patients, the stage IV analysis was moved to exploratory and reducing the number of patients needing to be enrolled in the study to approximately 44.
Investigators
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.
- •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
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.
Arms & Interventions
durvalumab
IV infusion once every 2 weeks for 4 total doses
Intervention: durvalumab
Outcomes
Primary Outcomes
Median modified Neoadjuvant Rectal (mNAR) Score
Time Frame: From the beginning of the study to time of surgical resection, assessed over an estimated 12 weeks
Compare Median modified Neoadjuvant Rectal (mNAR) Score to historic control using the Wilcoxon test
Secondary Outcomes
- Pathologic complete response rate to study therapy(At the time of surgical resection)
- Clinical complete response rate to study therapy(From one week prior to surgical resection up to time of surgical resection)
- Rate of negative circumferential margin(At the time of surgical resection)
- Sphincter function in patients with sphincter preserving surgery(From the time of surgical resection to 30 days after surgery)
- Severity of post-operative complications(From time of surgical resection to within 30 days post-operation)
- Frequency of adverse events assessed by CTCAE 4.0(From beginning of study therapy to 90 days after last dose of study therapy)