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

Plain English Summary

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 is a Phase 1 clinical trial sponsored by M.D. Anderson Cancer Center studying Advanced Solid Tumor, Non-small Cell Lung Cancers. This trial tests a combination of two drugs, adagrasib and olaparib, to see if they are safe and to find the right dose for patients with advanced solid tumors. It is for patients with specific genetic mutations (KRAS G12C and/or KEAP1) in their tumors, including certain types of lung, breast, pancreatic, ovarian, and uterine cancers. Participation involves taking the study drugs and regular check-ups to monitor safety and tumor response. Alternative treatments may include standard chemotherapy, targeted therapies, or immunotherapy, depending on the specific cancer type and prior treatments. The trial aims to enroll 1 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with advanced solid tumors that have specific KRAS G12C and/or KEAP1 mutations. Patients with advanced pancreatic, breast, uterine, ovarian, or non-small cell lung cancers that have progressed after at least one prior treatment. Individuals must have tumors that can be measured or evaluated, and generally good health with adequate organ function (blood counts, liver, and kidney function). Patients with other active cancers or conditions that could interfere with the study treatment or assessment may not be eligible. This trial is studying Advanced Solid Tumor, Non-small Cell Lung Cancers, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the frequency and severity of side effects, helping to determine a safe dose of the study drugs for future treatment. The specific primary outcome measures are: Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 (through study completion; an average of 1 year.). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial aims to address a need for new treatments for patients with specific genetic mutations in their advanced solid tumors, where current options may be limited. This research targets Advanced Solid Tumor, Non-small Cell Lung Cancers, where improved treatment options are needed.

Investor Insight

This trial explores a novel combination therapy for genetically defined cancers, potentially opening new treatment avenues and indicating investment in targeted oncology treatments. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of this combination therapy compared to other treatment options. Understand that participation involves regular clinic visits for drug administration, blood tests, scans, and monitoring for side effects. Be prepared for potential side effects and discuss any new or worsening symptoms with your healthcare team immediately. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 1 participants

Interventions

• DRUG: Adagrasib — Given by PO BID
• DRUG: Olaparib — Given by PO BID

Primary Outcomes

• Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 (through study completion; an average of 1 year.)

Full 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 

Trial Locations

• M D Anderson Cancer Center, Houston, Texas, United States

Frequently Asked Questions

Related Conditions

• Non-small Cell Lung Cancer
• Breast Cancer
• Pancreatic Cancer
• Ovarian Cancer
• Uterine Cancer
• Gynecological Cancers
• Solid Tumors
• KRAS Mutations
• KEAP1 Mutations
• PARP Inhibitors

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