Trial Title:
Regorafenib in Combination with Pembrolizumab or Pembrolizumab for MSI-H Colorectal Cancer
NCT ID:
NCT06006923
Condition:
MSI-H Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Pembrolizumab
Conditions: Keywords:
multi-kinase inhibitor
receptor tyrosine kinases
anti-PD1 blockade
immune checkpoint inhibitor
vascular endothelial growth factor receptor (VEGFR)
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Regorafenib
Description:
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.
Arm group label:
Pembrolizumab + Regorafenib
Other name:
BAY 73-4506
Other name:
Stivarga
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
An anti-PD1 blockade / immune checkpoint inhibitor treatment approved for patients with
high microsatellite instability (MSI-H) colorectal cancer (CRC) as first line therapy.
Arm group label:
Pembrolizumab
Arm group label:
Pembrolizumab + Regorafenib
Other name:
Keytruda
Summary:
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.
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.
Criteria for eligibility:
Criteria:
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
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
AdventHealth Orlando
Address:
City:
Orlando
Zip:
32804
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Rebecca Iorio, MD
Phone:
(407) 303-2024
Email:
rebecca.iorio@adventhealth.com
Contact backup:
Last name:
Mohamedtaki Tejani, MD
Facility:
Name:
Northwestern University
Address:
City:
Evanston
Zip:
60208
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Georgina Cardona, BS
Email:
georgina.cardona@northwestern.edu
Contact backup:
Last name:
Al B Benson, MD
Facility:
Name:
UPMC Hillman Cancer Center
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Status:
Recruiting
Contact:
Last name:
Clare Grzejka, RN, BSN
Phone:
412-623-4891
Email:
grzejkac@upmc.edu
Contact backup:
Last name:
Debra Diecks, RN, BSN
Phone:
412-623-8364
Email:
diecksda@upmc.edu
Contact backup:
Last name:
Ibrahim H Sahin, MD
Facility:
Name:
Fred Hutchinson Cancer Research Center
Address:
City:
Seattle
Zip:
98109
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Sonia Goyal Wadhera
Phone:
(206) 667-5000
Email:
sgoyal@seattlecca.org
Contact backup:
Last name:
Kjell Hansen
Email:
Khansen@seattlecca.org
Contact backup:
Last name:
Ronan Hsieh, MD
Start date:
June 26, 2024
Completion date:
June 2029
Lead sponsor:
Agency:
Ibrahim Halil Sahin
Agency class:
Other
Collaborator:
Agency:
Bayer
Agency class:
Industry
Source:
University of Pittsburgh
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06006923
