Trial Title:
Phase Ib Trial of the KRAS G12C Inhibitor Adagrasib (MRTX849) in Combination with the PARP Inhibitor Olaparib in Patients with KRAS G12C Mutated Advanced Solid Tumors, with a Focus on Gynecological, Breast, Pancreatic and KEAP1 Mutated Non-small Cell Lung Cancers
NCT ID:
NCT06130254
Condition:
Advanced Solid Tumor
Non-small Cell Lung Cancers
Conditions: Official terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Olaparib
Adagrasib
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Adagrasib
Description:
Given by PO BID
Arm group label:
Adagrasib+Olaparib
Other name:
MRTX849
Intervention type:
Drug
Intervention name:
Olaparib
Description:
Given by PO BID
Arm group label:
Adagrasib+Olaparib
Other name:
Lynparza™
Summary:
Evaluate safety and tolerability, while establishing the recommended dose of the
investigational drug combination of adagrasib and olaparib that can be given to
participants with advanced solid tumor(s) with a KRAS G12C and/or KEAP1 mutation.
Detailed description:
Primary Objectives
- To evaluate the safety and tolerability of adagrasib in combination with olaparib in
participants with KRAS G12C mutant advanced solid tumors.
- To establish the maximum tolerated dose and/or recommended phase 2 dose (MTD/RP2D)
of the combination in participants with KRAS G12C mutant advanced solid tumors.
Secondary Objectives
- To assess the preliminary antitumor activity of the combination of adagrasib in
combination with olaparib using objective response rate (ORR) = RECISTv1.1 complete
response plus partial response (CR+PR).
Exploratory Objectives
- To assess predictive biomarkers of response and resistance to the combination of
adagrasib with olaparib.
- To evaluate the pharmacodynamic profile of the combination of adagrasib and olaparib
in participants with KRAS G12C mutant advanced solid tumors.
- To assess potential mechanisms of response and resistance by comparing serially
collected circulating tumor DNA (ctDNA) samples and biopsies in responders and
non-responders.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Participants must be ≥ 18 years old and must fulfil all the following inclusion
criteria to be eligible for enrollment into the study.
1. Dose escalation cohort: Histologically confirmed diagnosis of a solid tumor
malignancy with a KRAS G12C mutation. Participants are eligible based on
detection of these mutations in tumor tissue or plasma circulating tumor DNA
(ctDNA) with a minimum VAF of 1%.
2. Dose expansion cohort 1: Histologically confirmed diagnosis advanced pancreatic
cancer with KRAS G12C mutation. Participants must have progressed on at least 1
prior line of standard systemic therapy and must be eligible based on detection
of KRAS G12C mutation in tumor tissue or ctDNA with a minimum VAF of 1%.
3. Dose expansion cohort 2: Histologically confirmed diagnosis of advanced breast
cancer with KRAS G12C mutation. Participants must have progressed on at least 1
prior line of standard systemic therapy and must be eligible based on detection
of KRAS G12C mutation in tumor tissue or ctDNA with a minimum VAF of 1%.
4. Dose expansion cohort 3: Histologically confirmed diagnosis of advanced uterine
or epithelial ovarian cancer with KRAS G12C mutation. Participants must have
progressed on at least 1 prior line of standard systemic therapy and must be
eligible based on detection of KRAS G12C mutation in tumor tissue or ctDNA with
a minimum VAF of 1%.
5. Dose expansion cohort 4: Histologically confirmed diagnosis of NSCLC with KRAS
G12C and KEAP1 co-mutations. Participants must have progressed on at least 1
prior line of standard systemic therapy and must be eligible based on detection
of KRAS G12C and KEAP1 co-mutations in tumor tissue or plasma circulating tumor
DNA (ctDNA) with a minimum VAF of 1%.
6. Unresectable or metastatic disease and for which standard curative or
palliative measures do not exist or are no longer effective.
7. Participants must have evaluable or measurable disease per RECIST v1.1 for the
dose escalation cohort and must have measurable disease per RECIST v1.1 for
dose expansion cohorts 1-4.
8. Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the investigational regimen are eligible for this trial.
9. Life expectancy of at least 3 months.
10. Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or,
investigational agent) and radiation therapy discontinued at least 2 weeks
before first dose date.
11. Eastern Cooperative Oncology Group (ECOG) performance status in 0 or 1 (see
Appendix 1).
12. Laboratory values within the screening period:
1. Absolute neutrophil count ≥ 1.5 x 109/L
2. Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
3. Hemoglobin ≥ 10 g/dL, in the absence of transfusions for at least 28 days
4. Total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) (if associated with
liver metastases or Gilbert's disease, ≤ 3 x ULN)
5. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN
(if associated with liver metastases, ≤ 5 x ULN)
6. Creatinine clearance ≥51mL/min calculated using a validated prediction
equation:
Estimated GFR= (140-age(years)∙ Weight (Kg)∙F)/(serum creatine (mgdL)∙72),
where F=0.85 for females and F=1 for males.
13. The effects of adagrasib on the developing human fetus are unknown. For this
reason and because the therapeutic agents used in this trial are known to be
teratogenic, women and men, who are sexually active and of childbearing
potential, must agree to use two highly effective forms of contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry,
for the duration of study participation, and for 6 months following termination
of the study treatment (MDA Policy CLN 1114). This includes all female
participants, between the onset of menses between 18 and 55 years, unless the
patient presents with an applicable exclusionary factor which may be one of the
following: (i) Postmenopausal (no menses in greater than or equal to 12
consecutive months); (ii) History of hysterectomy or bilateral
salpingo-oophorectomy; (iii) Ovarian failure (Follicle Stimulating Hormone and
Estradiol in menopausal range, who have received Whole Pelvic Radiation
Therapy); (iv) History of bilateral tubal ligation or another surgical
sterilization procedure; (v) radiation-induced oophorectomy with last menses at
least 1 year ago; and (vi) chemotherapy-induced menopause with at least 1 year
interval since last menses. Approved methods of birth control are as follows:
Hormonal contraception (i.e. birth control pills, injection, implant,
transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or
hysterectomy, Subject/Partner post vasectomy, Implantable or injectable
contraceptives, and condoms plus spermicide. Not engaging in sexual activity
for the total duration of the trial and the drug washout period is an
acceptable practice; however periodic abstinence, the rhythm method, and the
withdrawal method are not acceptable methods of birth control. Should a woman
become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician
immediately.
14. Men treated or enrolled on this protocol must also agree to use adequate
contraception and avoid donating sperm prior to the study, for the duration of
study participation, and 6 months after completion of the trial.
15. Prior treatment with a therapy targeting PARP or KRAS G12C mutation is
permitted.
16. Ability to understand and the willingness to sign a written informed consent
document.
17. Willing to comply with clinical trial instructions and requirements.
Exclusion Criteria:
- Participants presenting with any of the following will not be included in the study:
1. Active brain metastases. Patients are eligible if brain metastases are
adequately treated and patients are neurologically stable (which is assessed in
a case-by-case by the treating physician based on the likelihood of central
nervous system (CNS) activity - except for residual signs or symptoms related
to the CNS treatment- and by the lack of corticosteroid dosing or by having a
stable or decreasing dose of ≤ 10 mg daily prednisone, or equivalent) for at
least 2 weeks prior to enrollment.
2. Participants with carcinomatous meningitis.
3. Participants with myelodysplastic syndrome/acute myeloid leukemia or with
features suggestive of MDS/AML.
4. Participants who have not recovered from adverse events due to prior
anti-cancer therapy (i.e., have residual toxicities > Grade 1), excluding
alopecia.
5. History of significant hemoptysis or hemorrhage within 4 weeks of the first
dose date.
6. Undergone major surgery within 4 weeks of first dose date, or not recovered
from any major surgery that occurred >2 weeks before starting study treatment.
7. Undergone allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
8. History of intestinal disease, inflammatory bowel disease, major gastric
surgery, or other gastrointestinal conditions (e.g., uncontrolled nausea,
vomiting, malabsorption syndrome) likely to alter absorption of study treatment
or result in inability to swallow oral medications.
9. Any of the following cardiac abnormalities:
1. Unstable angina pectoris or myocardial infarction within 6 months prior to
enrollment
2. Congestive heart failure NYHA ≥ Class 3 within 6 months prior to
enrollment
3. Left ventricular ejection fraction (LVEF) < 50%
4. QTc > 480 milliseconds or medical or immediate family history of
congenital Long QT Syndrome
5. Symptomatic or uncontrolled atrial fibrillation or other arrhythmia within
6 prior to enrollment
6. History of uncontrolled ventricular arrhythmia, recent (within 6 months)
myocardial infarction
10. History of stroke or transient ischemic attack within 6 months prior to
enrollment.
11. Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors
listed in Section 5.5 and Appendix 4, Table 23. The required washout period
prior to starting study treatment is 2 weeks.
12. Concomitant use of known strong or moderate CYP3A inducers listed in Section
5.5 and Appendix 4, Table 23. The required washout period prior to starting
study treatment is 5 weeks.
13. Use of a medication with any of the following characteristics, which cannot be
switched to an alternative treatment prior to study entry:
1. Substrate of P-gp with narrow therapeutic index
2. Strong inhibitor of BCRP
3. Proton pump inhibitor
4. Known risk of QT prolongation or Torsades de Pointes
5. Any substances listed in Section 6.3
14. Known or suspected presence of another malignancy, unless curatively treated,
with no evidence of disease for ≥5 years with the exception of adequately
treated non-melanoma skin cancer, curatively treated in situ cancer of the
cervix, ductal carcinoma in situ (DCIS), Stage 1-grade 1 endometrial carcinoma.
15. Known history of human immunodeficiency virus (HIV) infection or acute or
chronic
Hepatitis B or C infection. Note that the following are permitted:
1. Participants treated for hepatitis C with no detectable viral load;
2. Patients treated for HIV with no detectable viral load for at least 1
month prior to enrollment while on a stable regimen of agents that are not
strong inhibitors of CYP3A4
16. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented
within the 28-day screening period prior start of study drug.
17. Breast-feeding or planning to breast feed during the study or within 6 months
after study treatment.
18. 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 the results.
19. History of uncontrolled ventricular arrhythmia, recent (within 6 months)
myocardial infarction, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral
lung disease on High Resolution Computed Tomography (HRCT) scan
20. Participants with a known hypersensitivity to olaparib or any of the excipients
of the product
21. Patients that received live virus and live bacterial vaccines within 3 days of
trial enrollment.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Timothy Yap, M D
Phone:
713-563-1784
Email:
TYap@mdanderson.org
Start date:
January 30, 2024
Completion date:
August 25, 2030
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
Agency class:
Other
Collaborator:
Agency:
Mirati Therapeutics Inc.
Agency class:
Industry
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/NCT06130254
http://www.mdanderson.org
