A Phase 1 Study of INCB099280 in Combination With Adagrasib in Adults With Advanced Solid Tumors Harboring a KRASG12C Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Incyte Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 May 2024 → 11 Jul 2025

Decision date (initial)

2024-03-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Incyte Corporation

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

• To evaluate the safety and tolerability of INCB099280 in combination with adagrasib.
• To establish the MTD or identify RDE(s) for the combination of INCB099280 and adagrasib.

Secondary objectives 3

1. To characterize the PK of INCB099280 and adagrasib when administered in combination.
2. To assess the antitumor activity of INCB099280 in combination with adagrasib in participants with KRASG12C-mutant advanced solid tumors, including NSCLC and CRC.
3. To assess the antitumor activity of INCB099280 in combination with adagrasib in participants with KRASG12C-mutant advanced solid tumors, including NSCLC and CRC.

Conditions and MedDRA coding

Advanced Solid Tumors Harboring a KRASG12C Mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Ability to comprehend the participant information and willingness to sign a written ICF for the study.
2. Men and women 18 years of age or older at the time of signing the ICF.
3. KRASG12C-mutated solid malignancy determined by a sponsor-approved assay using either tumor tissue or ctDNA.
4. Histologically confirmed malignant solid tumor with locally advanced and/or metastatic disease. a. Only participants with NSCLC will be enrolled into Part 2 Cohort A. b. Only participants with CRC will be enrolled into Part 2 Cohort B.
5. Part 1: Disease progression on or after at least 1 prior systemic treatment. Participants must have received all available local standard of care therapies.
6. Part 2 (Cohort A): Received at least 1 platinum-containing chemotherapy regimen that may include an anti–PD-1 inhibitor.
7. Part 2 (Cohort B): Received at least 1 line of systemic therapy.
8. Measurable disease according to RECIST v1.1.
9. Known PD-L1 expression level in tumor. The PD-L1 expression level may have been determined at any point in the disease course using a commercially available assay or can be tested locally during the screening process (using a commercially available assay) and the results reported to the sponsor. If PD-L1 expression is unknown or cannot be tested locally, participants must be willing to provide tumor tissue (fresh or archival).
10. ECOG performance status of 0 or 1.
11. Estimated life expectancy > 3 months.
12. Willingness to avoid pregnancy or fathering children based on the criteria below. a. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 100 days after the last dose of study drug (or longer as appropriate based on country-specific requirements) and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed. b. Women of childbearing potential must do the following:  Have a negative serum pregnancy test at screening and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 190 days after the last dose of study treatment. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.  Refrain from donating oocytes from 30 days before the first dose of study drug until 90 days after the last dose. c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age) are eligible.

Exclusion criteria 34

1. Another malignancy that is progressing or has progressed within the past 3 years and/or that requires treatment. Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, early-stage endometrial cancer that has been definitively treated, superficial bladder cancer, Gleason 6/7 treated prostate cancer, and ductal carcinoma in situ or lobular carcinoma in situ of the breast.
2. CNS metastases requiring treatment and/or leptomeningeal disease. a. Participants with untreated CNS metastases that are symptomatic, who require increasing doses of steroids and/or a steroid dose of more than 1 mg of dexamethasone daily (or equivalent), or with lesions with a significant amount of surrounding edema. b. Participants with previously treated CNS metastases that are progressing, who are not clinically stable within 2 weeks of the initiation of study treatment, or who require increasing doses of steroids and/or a steroid dose of more than 1 mg of dexamethasone daily (or equivalent).
3. Part 2 only: Prior treatment with an approved or investigational agent targeting KRASG12C.
4. Prior receipt of an anti–PD-L1—containing therapy and 6 months has not elapsed prior to the first dose of study treatment.
5. Toxicity from prior therapy that has not recovered to ≤ Grade 1 or baseline (with the exception of anemia not requiring transfusion support and any grade of alopecia). Endocrinopathy not adequately controlled on replacement therapy should be discussed with the medical monitor.
6. Received a radical dose of radiotherapy within 6 months of the first dose of study treatment and in the opinion of the radiation oncologist, the side effects have not resolved sufficiently to allow the administration of the study drug as planned.
7. Participation in another interventional clinical study.
8. Treatment with anticancer medications or investigational drugs within the following intervals before the first administration of study drug: a. At least 14 days for chemotherapy or targeted small-molecule therapy. b. At least 28 days for a prior monoclonal antibody. c. At least 28 days or 5 half-lives (whichever is longer) for all other investigational study drugs or devices.
9. Impaired cardiac function or clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months before the start of study treatment, New York Heart Association Class III or IV CHF, clinically significant or uncontrolled arrhythmias, or a cerebrovascular accident within 6 months of the start of study treatment.
10. History or evidence of interstitial lung disease, including noninfectious pneumonitis.
11. Presence of a GI condition that may affect drug absorption.
12. Active autoimmune disease requiring systemic treatment, including corticosteroids exceeding a daily dose of 10 mg of prednisone or equivalent.
13. A diagnosis of immunodeficiency or receiving chronic systemic steroid therapy exceeding a daily dose of 10 mg of prednisone or equivalent.
14. HIV infection with a CD4+ T-cell count < 200 cells/µL and/or a detectable viral load per parameters of assay and/or on an ART regimen containing a moderate or potent CYP3A4/CYP3A5 inhibitor or inducer and/or on a new ART regimen for less than 28 days prior to the initiation of study treatment.
15. Active infection, including tuberculosis, requiring systemic therapy, with the exception of HIV as noted in Exclusion Criterion 14.
16. History of organ transplantation, including allogeneic stem cell transplantation.
17. Known hypersensitivity or severe reaction to any component of study drug or formulation components.
18. Major surgery within 4 weeks of the start of study therapy or postoperative complications preventing the participant from adhering to protocol assessments and procedures.
19. Presence of GI conditions that may affect drug absorption, as well as those that interfere with GI transit, including gastric bypass surgery, gastric sleeve, or gastric band.
20. Inability to swallow tablets.
21. Receipt of systemic antibiotics within 28 days of the first dose of study treatment.
22. Probiotic usage during screening and throughout the study treatment period.
23. Receipt of a live-attenuated vaccine (such as measles, mumps, and rubella; chickenpox; some zoster; yellow fever; rabies; BCG; and typhoid vaccines) within 28 days of the planned start of study drug. Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live-attenuated vaccines and are not allowed. Note: If enrolled, participants should not receive live-attenuated vaccines during the study and up to 90 days after the last dose of study treatment (see Section 6.7.3).
24. Medication with any of the following characteristics that cannot be discontinued prior to the start of study treatment: moderate and potent CYP3A4/CYP3A5 inhibitors or inducers (see Appendix B), CYP3A substrates with a narrow therapeutic index, P-gp substrates with a narrow therapeutic index, inhibitors of BCRP, proton pump inhibitors, or known risk of torsades de pointes. Note: A washout period ≥ 14 days before the first dose of INCB099280 is required for prior treatment with CYP3A4/CYP3A5 inhibitors and inducers.
25. Unable to be weaned off of a prohibited medication as described in Section 6.7.3 before the initiation of study treatment.
26. Participants with laboratory values at screening as defined in Table 9.
27. Clinically significant ECG abnormality.
28. An average QTcF interval > 450 milliseconds on triplicate ECG.
29. Systolic dysfunction with an LVEF < 53%.
30. Active HBV or HCV infection defined as follows (testing must be performed to determine eligibility): a. Detectable HBV DNA b. Chronic HBV infection with active disease meeting the criteria for anti-HBV therapy in participants who are not on a suppressive antiviral therapy prior to initiation of or while receiving study treatment. c. A positive HCV antibody and quantitative HCV RNA result greater than the lower limit of detection for the assay.
31. Is pregnant or expecting to conceive or breastfeeding starting with the screening visit through 190 days after the last dose of study treatment or expecting to father children starting with the screening visit through 100 days after the last dose of study treatment.
32. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending all planned study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
33. Known history of drug-induced liver injury; alcoholic liver disease; nonalcoholic steatohepatitis; primary biliary cirrhosis; or ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver, or portal hypertension.
34. The following participants are excluded in France: vulnerable populations according to article L.1121-6 of the French Public Health Code and adults under legal protection, or who are unable to express their consent per article L.1121-8 of the French Public Health Code, not affiliated to a social security per article L.1121-8-1 of the French Public Health Code.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. DLTs.
2. TEAEs.
3. Impact of TEAEs on study drug administration, assessed by treatment interruptions, dose reductions, and permanent discontinuation.

Secondary endpoints 6

1. Descriptive summary of PK concentration data for INCB099280 and adagrasib.
2. INCB099280 PK parameters including Cmax,ss, Tmax,ss, Cmin,ss, AUC0-12h, CL/F, and Vz/F from observed INCB099280 plasma concentration time profiles, summarized and analyzed for DDIs.
3. Objective response, defined as having a best overall response of CR or PR assessed per RECIST v1.1 by the investigator.
4. Disease control, defined as having a best overall response of CR, PR, or SD ≥ 15 weeks (from the start of treatment) assessed per RECIST v1.1 by the investigator.
5. DOR, defined as the time from the first CR or PR until disease progression (assessed per RECIST v1.1 by the investigator) or death from any cause, whichever occurs earlier.
6. Six-month and 12-month PFS, defined as absence of disease progression (assessed per RECIST v1.1 by the investigator) or death from any cause from start of treatment to 6 or 12 months.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Incyte Corp.

Sponsor organisation

Incyte Corp.

Address

1801 Augustine Cut Off

City

Wilmington

Postcode

19803-4404

Country

United States

Scientific contact point

Organisation

Incyte Corp.

Contact name

Clinical Trial Information

Public contact point

Organisation

Incyte Corp.

Contact name

Clinical Trial Information

Third parties 3

Sponsor responsibilities

Article 77 compliance

Incyte Corp.

Contact point sponsor

Incyte Corp.

Article 77 implementation

Incyte Corp.

Locations

3 EU/EEA countries · 22 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications