Trial Title:
A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations
NCT ID:
NCT06412198
Condition:
Metastatic Colorectal Cancer
KRAS G12C Mutations
Conditions: Official terms:
Colorectal Neoplasms
Cetuximab
Cemiplimab
Adagrasib
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cetuximab
Description:
Given by IV
Arm group label:
Expansion
Arm group label:
Lead-In
Other name:
ERBITUX
Intervention type:
Drug
Intervention name:
Cemiplimab
Description:
Given by IV
Arm group label:
Expansion
Arm group label:
Lead-In
Intervention type:
Drug
Intervention name:
Adagrasib
Description:
Given by PO
Arm group label:
Expansion
Arm group label:
Lead-In
Summary:
To learn if the drug combination of adagrasib, cetuximab, and cemiplimab can help to
control metastatic CRC with KRAS G12C mutations.
Detailed description:
Primary Objective
• To determine the objective response rate of the adagrasib, cetuximab, and cemiplimab
combination for treatment of advanced KRAS G12C MT CRC that has progressed on at least
one line of prior systemic chemotherapy.
Secondary Objectives
- To estimate duration of response (DOR), progression free survival (PFS), and overall
survival (OS) for the combination of adagrasib, cetuximab, and cemiplimab in
participants with advanced KRAS G12C MT CRC that has progressed on at least one line
of prior systemic chemotherapy.
- To estimate the safety and tolerability of the combination of adagrasib, cetuximab,
and cemiplimab in participants with advanced KRAS G12C MT CRC that has progressed on
at least one line of prior systemic chemotherapy.
Exploratory Objectives
- To assess predictive biomarkers of response and resistance to the combination of
adagrasib, cetuximab, plus cemiplimab.
- To assess mechanisms of tumor cell adaptation upon treatment with the combination of
adagrasib, cetuximab, plus cemiplimab.
- To determine mechanisms of acquired resistance to the combination of adagrasib,
cetuximab, plus cemiplimab.
- To assess the effect of the combination of adagrasib, cetuximab plus cemiplimab on
the immune tumor microenvironment.
- To generate cell lines and participant derived xenograft (PDX) models from tumor
samples.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Histologically confirmed diagnosis of advanced/metastatic microsatellite stable
colorectal cancer with KRASG12C mutation with 1+ prior line(s) of therapy
- Confirmed KRASG12C mutation status. If a molecular profiling report is not
available, a representative paraffin-embedded tumor block or a minimum of 10
unstained slides will be requested for retrospective KRASG12C mutation testing.
- Unresectable or metastatic disease.
- Participants must have received at least one prior line of chemotherapy for
metastatic disease with progression on treatment or intolerance to therapy.
- Presence of measurable disease per RECIST 1.1
- Willingness to participate in on-study related procedures, including mandatory
biopsies (one baseline and one on-treatment biopsy).
- Age ≥ 18 years. Because no dosing or adverse event data are currently available on
the use of the proposed combination in patients <18 years of age, children are
excluded from this study.
- Able to take oral medications.
- Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or
investigational agent) and radiation therapy discontinued at least 7 days before
first dose.
- Recovery from the treatment-related adverse effects of prior therapy at the time of
enrollment to ≤ Grade 1 (excluding alopecia and prior oxaliplatin-induced
neuropathy).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Laboratory values within the screening period:
- Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
- Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
- Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks
- Total bilirubin ≤ 1.5x upper limit of normal (ULN) (if associated with
Gilbert's disease or UGT1A1*28 homozygosity, ≤ 3x ULN)
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0x ULN (if
associated with liver metastases ≤5x ULN)
- Calculated creatinine clearance (determined as per Cockcroft-Gault) ≥ 60mL/min
at screening
- Completed informed consent process, including signing of IRB-approved informed
consent form.
- Willing and able to comply with clinical trial instructions and requirements.
Individuals lacking the ability, based on reasonable medical judgment, to understand
and appreciate the nature and consequences of participation in this study will not
be eligible for participation.
- Participants who are biologically capable of having children and sexually active
must agree to use an acceptable method of contraception for the duration of the
treatment period and for at least 6 months after the last dose of study treatment.
The Investigator will counsel the patient on selection of contraception method and
instruct the participant in its consistent and correct use. Examples of acceptable
forms of contraception include:
- Oral, inserted, injected or implanted hormonal methods of contraception,
provided it has been used for an adequate period of time to ensure
effectiveness.
- Correctly placed copper containing intrauterine device (IUD).
- Male condom or female condom used WITH a spermicide.
- Male sterilization with confirmed absence of sperm in the post-vasectomy
ejaculate.
- Bilateral tubal ligation or bilateral salpingectomy.
- The Investigator will instruct the participant to call immediately if the selected
birth control method is discontinued or if pregnancy is known or suspected.
- Note: Women are considered post-menopausal and/or not of child bearing
potential if they have had 12 months of natural (spontaneous) amenorrhea with
an appropriate clinical profile (e.g., age appropriate, history of vasomotor
symptoms) or have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least 6 months ago. In case of any
ambiguity, the reproductive status of the woman should be confirmed by hormone
level assessment.
Exclusion Criteria:
- Prior PD1 or CTLA4 inhibition therapy
- Prior KRASG12C inhibition therapy
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment
- Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered
a form of systemic treatment
- Active brain metastases, unless adequately treated and participant is neurologically
stable (except for residual symptoms of central nervous system treatment) for at
least 2 weeks prior to enrollment without corticosteroids or are on a stable or
decreasing dose of ≤ 10 mg daily prednisone (or equivalent)
- Ongoing need for a medication with any of the following characteristics that cannot
be switched to alternative treatment within 10 days prior to study entry: known risk
of QTc prolongation or Torsades de Pointes; substrate of CYP3A with a narrow
therapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; strong
inhibitor of BCRP; strong inhibitor or inducer of CYP2C19; and proton pump
inhibitors
- Major surgery within 4 weeks of the first dose of any study drug
- History of intestinal disease or major gastric surgery likely to alter absorption of
study treatment (to be determined by the treating physician)
- Pregnancy. Women of child-bearing potential must have a negative serum or urine
pregnancy test during screening
- Breast-feeding or planning to breast feed during the study or within 6 months after
end of treatment.
- Participants with symptomatic leptomeningeal disease.
- Major surgery within 4 weeks of first dose of any study drug.
- History of intestinal disease or major gastric surgery likely to alter absorption of
study treatment, to be determined by the treating physician
- Known human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B
(HBV) or C (HCV) infection as tested in a CLIA certified lab using a positive HIV
antibody test. For Hepatitis B and C, an antigen that is drawn and positive. Note
that the following are permitted:
- Participants treated for HIV with no detectable viral load on current regimen for at
least 1 month prior to randomization;
- Note: Please refer to exclusion criteria regarding drug-drug interactions of
concomitant anti-HIV agents, and in particular CYP3A substrates.
- Participants with prior HBV infections who are:
- considered to have past or resolved HBV infection, defined as the presence of
hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen
[HBsAg]; or
- considered to be in an inactive HBV carrier state, defined as HBsAg-positive with
normal ALT, and HBV DNA < 2,000 IU/mL or < 10,000 copies/mL;
- Note: For participants in an inactive HBV carrier state or with a resolved HBV
infection, the risk of HBV reactivation should be considered and the need for
anti-HBV prophylaxis prior to randomization should be carefully assessed in
accordance with local guidelines.
- Participants treated for HCV with no detectable viral load.
- Any serious illness, uncontrolled inter-current illness, psychiatric illness, active
or uncontrolled infection, or other medical history, including laboratory results,
which, in the investigator's opinion, would be likely to interfere with the
participant's participation in the study, or with the interpretation of results.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Massachusetts General Hospital Cancer Center
Address:
City:
Boston
Zip:
02114
Country:
United States
Status:
Not yet recruiting
Contact:
Last name:
Ryan Corcoran, MD
Phone:
617-726-8599
Email:
rbcorcoran@mgb.org
Contact backup:
Last name:
Ryan Corcoran, MD
Facility:
Name:
MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Christine Parseghian, MD
Phone:
(713) 795-9280
Email:
cparseghian@mdanderson.org
Contact backup:
Last name:
Christine Parseghian, MD
Start date:
August 28, 2024
Completion date:
March 1, 2028
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
Agency class:
Other
Source:
M.D. Anderson Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06412198
http://www.mdanderson.org
