Regorafenib in Combination With Pembrolizumab or Pembrolizumab for MSI-H Colorectal Cancer

Randomized Trial of Regorafenib in Combination With Pembrolizumab or Pembrolizumab Monotherapy With an Efficacy Lead-in of Regorafenib and Pembrolizumab for Patients With MSI-H Colorectal Cancer

This is a trial of Regorafenib in combination with pembrolizumab for patients with MSI-H colorectal cancer consisting of lead-in phase examining preliminary efficacy and safety, followed by a randomized phase to further examine efficacy.

Study Overview

• Status: Not yet recruiting
• Conditions: MSI-H Colorectal Cancer
• Intervention / Treatment: Drug: Regorafenib; Drug: Pembrolizumab

Detailed Description

Regorafenib is a multi-kinase inhibitor that targets several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR). Regorafenib may also have immunomodulatory affect in the tumor microenvironment. Preclinical and early clinical studies indicate there is a potential for synergistic activity of regorafenib with immune checkpoint inhibitors that can be leveraged to augment antitumor immunity. Pembrolizumab, anti-PD1 blockade, has been approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy. However, there is still an unmet need to enhance the efficacy of immune checkpoint inhibitors for patients with MSI-H colorectal cancer. The efficacy of TKI and immune checkpoint inhibitor combination have been shown in clinical studies for solid tumors particularly for those that are responsive to immune checkpoint inhibitors therapy. Therefore, there is strong rationale for the combination of regorafenib and pembrolizumab in MSI-H colorectal cancer in which there is increased VEGF activity compared to MSS counterpart. A recent retrospective study showed significantly improved response to regorafenib among patients with MSI-H colorectal cancer, compared to patients with MSS colorectal cancer. Collectively, this combination may increase anti-tumor immune response and clinical effectiveness of immunotherapy for patients with MSI-H colorectal cancer. Based on prior clinical trials, the target regorafenib dose in this study is determined to be 90 mg. However, patients in the lead-in phase will receive regorafenib 60 mg in combination with 200mg of pembrolizumab Q3 weeks in the first cycle to increase tolerance and study compliance. The dose of regorafenib will be increased to 90 mg by Cycle 2. An interim analysis will be performed after completion of data collection for the lead-in phase. Target enrollment for the lead-in phase is approximately 22 patients. Following the futility analysis in lead-in phase, the randomized phase target enrollment is determined to be 66 patients per arm, for a total trial enrollment of 154 participants. Patients who received 3 or less cycles of chemotherapy prior to the determination of MMR-D and MSI-H disease can be enrolled in this trial.

• Study Type: Interventional
• Enrollment (Estimated): 154
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clare Grzejka, RN, BSN; Phone Number: 412-623-4891; Email: grzejkac@upmc.edu
• Study Contact Backup: Name: Debra Diecks, RN, BSN; Phone Number: 412-623-8364; Email: diecksda@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
      • Contact: Clare Grzejka, RN, BSN; Phone Number: 412-623-4891; Email: grzejkac@upmc.edu
      • Contact: Debra Diecks, RN, BSN; Phone Number: 412-623-8364; Email: diecksda@upmc.edu
      • Principal Investigator: Ibrahim H Sahin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed mismatch repair deficient or microsatellite instability high advanced stage colorectal cancer
2. Measurable disease (per RECIST v1.1)
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
4. Age > 18
5. The patient must be able to swallow oral medication.

6. Adequate organ function based on the following lab assessments:

   1. ANC must be ≥ 1500/mm3
   2. platelet count must be ≥ 100,000/mm3
   3. WBC count ≥ 2.5 × 109 /L
   4. Hemoglobin must be ≥ 9 g/dL
   5. Alkaline phosphatase ≤ 2.5× upper limit of normal (ULN) with the exception of patients with documented liver or bone metastases who should have ALP ≤ 5.0× ULN
   6. AST and ALT ≤ 2.5× ULN with the exception of patients with documented liver metastases who may have AST and/or ALT ≤ 5.0× ULN
   7. International normalized ratio (INR) ≤ 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless receiving treatment with therapeutic anticoagulation
   8. Total bilirubin ≤ 1.5× ULN (≤ 3× ULN if Gilbert syndrome present)
   9. Serum albumin ≥ 2.8 g/dL or 28 g/L
   10. Creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula) or creatinine ≤ 1.5× ULN
7. No more than three cycles of prior fluoropyrimidine-based chemotherapy including folinic acid, fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan (FOLFIRI); and, folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) excluding adjuvant treatment
8. Patients (male or female) of reproductive potential must agree to use an effective method of contraception (as discussed with treating physician) from the time consent is signed, during study therapy, and for at least 8 weeks after the last dose of study therapy.
9. Patients who received no more than 1 cycle of pembrolizumab monotherapy will be still eligible to be enrolled in lead in phase of the trial

Exclusion Criteria:

1. Prior anti-programmed death 1 (anti-PD-1) or anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) based therapy
2. More than 3 cycles of chemotherapy or progression of disease on first line therapy excluding adjuvant treatment and any systemic anticancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study treatment
3. Active autoimmune disease
4. Pregnant or lactating females
5. Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV); patients with undetectable viral load and CD4 count > 200 will be eligible for enrollment
6. Active untreated brain metastasis
7. Uncontrolled hypertension (HTN: systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg on repeated measurements) and cardiovascular events within 12 months of start of treatment
8. Active infection or chronic infection requiring chronic suppressive antibiotics
9. No active cancer such as colon cancer other than adenocarcinoma (e.g., sarcoma, lymphoma, carcinoid) within 1 year
10. Patients with severe hepatic impairment (Child-Pugh C) are excluded as regorafenib has not been studied in this population and exposure might be increased in these patients
11. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
12. Non-healing wound, non-healing ulcer, or non-healing bone fracture
13. Patients with evidence or history of any bleeding diathesis, irrespective of severity

14. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication:

    1. Major surgical procedure or significant traumatic injury within 28 days before start of study medication
    2. Non-healing wound, non-healing ulcer, or non-healing bone fracture
    3. Patients with evidence or history of any bleeding diathesis, irrespective of severity
    4. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pembrolizumab + Regorafenib; Pembrolizumab: 200mg, Q3 weeks Regorafenib: 60mg Cycle 1 Day 1 90 mg Cycle 2 Day 1	Drug: Regorafenib; A multi-kinase inhibitor that targets several receptor tyrosine kinases including vascular endothelial growth factor receptor (VEGFR), which may also have immunomodulatory affect in the tumor microenvironment.; Other Names: BAY 73-4506; Stivarga; Drug: Pembrolizumab; An anti-PD1 blockade / immune checkpoint inhibitor treatment approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy.; Other Names: Keytruda
Active Comparator: Pembrolizumab; Pembrolizumab: 200mg, Q3 weeks	Drug: Pembrolizumab; An anti-PD1 blockade / immune checkpoint inhibitor treatment approved for patients with high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy.; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR), Lead-in Phase	Percentage of patients with partial response (PR) or complete response (CR) to the treatment per RECIST 1.1. criteria. v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Up to 12 months (lead-in phase)
Progression-free Survival (PFS), Randomize Phase	Median number of months from time of randomization to the date of disease progression or death from any cause. Per RECISIT v1.1: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events and Serious Adverse Events Related to Treatment	Percentage of patients that experience Adverse Events (AEs) and/or Serious Adverse Events (SAEs) related to study treatment, per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The maximum grade for each type of toxicity will be recorded for each patient.	Up to 24 months (lead-in phase)
Adverse Events and Serious Adverse Events Related to Treatment	Percentage of patients that experience Adverse Events (AEs) and/or Serious Adverse Events (SAEs) related to study treatment, per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The maximum grade for each type of toxicity will be recorded for each patient.	Up to 24 months (beginning at start of post lead-in phase)
Progression-free Survival (PFS), Lead-In Phase	Median number of months from time of randomization to the date of disease progression or death from any cause. Per RECISIT v1.1: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.	Up to 24 months
Overall Survival (OS)	Median number of months from start of treatment to death from any cause.	Up to 48 months (lead-in phase)
Overall Survival (OS)	Median number of months from time of randomization to death from any cause.	Up to 24 months (beginning at start of post lead-in phase)
Objective Response Rate (ORR), Randomized Phase	Percentage of patients with partial response (PR) or complete response (CR) to the treatment per RECIST 1.1. criteria. v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.	Up to 12 months (beginning at start of post lead-in phase)

Collaborators and Investigators

• Sponsor: Ibrahim Halil Sahin
• Collaborators: Bayer
• Investigators: Principal Investigator: Ibrahim H Sahin, MD, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: August 17, 2023
• First Submitted That Met QC Criteria: August 17, 2023
• First Posted (Actual): August 23, 2023

Study Record Updates

• Last Update Posted (Actual): May 6, 2024
• Last Update Submitted That Met QC Criteria: May 3, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: immune checkpoint inhibitor; multi-kinase inhibitor; receptor tyrosine kinases; anti-PD1 blockade; vascular endothelial growth factor receptor (VEGFR)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: HCC 23-041

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes