IRB Study Number 24-1211
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
Monotherapy Dose Escalation
• To assess the safety and tolerability of LY4066434 administered as monotherapy
Dose Optimization
• To assess the safety and determine the optimal dose(s) of LY4066434 administered as a monotherapy and in combination with other therapies
Secondary Objectives
• To assess the preliminary antitumor activity of LY4066434 when administered alone or in combination with other therapies using RECIST v1.1
• To characterize the PK properties of LY4066434 when administered alone or in combination with other therapies in participants with advanced solid tumors with KRAS mutation
Inclusion Criteria
Age
1) Must be ≥18 years of age, or age of majority if higher per local regulations, at the time of enrollment.
Type of Participant and Disease Characteristics
2) Have evidence of KRAS G12C, G12D, G12V, G12A, G12S, or G13D mutation in tumor tissue or circulating tumor DNA as determined by molecular testing performed at a CLIA, ISO/IEC, CAP, or other similar certified laboratory as per local guidelines including, but not limited to, IVDR compliance as applicable.
3) All Parts: Histological or cytologically proven diagnosis of a locally advanced, unresectable, and/or metastatic solid tumor cancer. Disease must not be suitable for curative intent surgery or radiation.
In dose optimization (including safety lead-in) participants must have a diagnosis of:
• Part B: PDAC
• Part C: CRC
• Part D: NSCLC (mixed small cell/non-small cell histology is not permitted)
• Part E: solid tumor other than PDAC, CRC, or NSCLC
4) Individuals should only be enrolled if, in the Investigator’s judgment, the individual is an appropriate candidate to initiate the planned treatment regimen as specified in the table below. Individuals are considered treatment naïve if they have received no more than 1 prior cycle of treatment provided it was the same regimen/doses as specified in the part they are enrolling in and initiated within 28 days prior to the start of treatment. If a dose modification is required or DLT-equivalent toxicity is observed the individual is not eligible.
5) Have measurable disease per RECIST 1.1
6) Have an ECOG performance status of ≤1
7) Must have adequate organ function as defined in the following table: (See protocol) Contraception
8) WOCBP and men with partners who are WOCBP must agree to use a highly effective method of birth control (see Section 13.1) during trial treatment and for at least 6 months following the last dose of trial intervention. Sperm and egg donation are prohibited during the duration of participation in this protocol and for 6 months after the last dose of trial intervention.
9) WOCBP must have a negative serum pregnancy test documented within 14 days prior to initiation of treatment and a negative urine pregnancy test obtained on C1D1 if the serum pregnancy test was obtained more than 7 days prior to C1D1.
10) Must not be pregnant and/or planning to breastfeed during the trial or within 180 days of the last dose of trial intervention.
Informed Consent
11) The individual must be capable of demonstrating an understanding of the nature, significance, and implications of participation in the trial and giving signed informed consent as described in Section 10.3, which includes compliance with the requirements
and restrictions listed in the ICF and in this protocol.
Other Criteria
12) Must be able to swallow tablets.
13) Must be able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of trial participation.
Exclusion Criteria
Medical Conditions
14) Known actionable tumor-specific co-occurring driver alteration with a corresponding approved agent such as but not limited to EGFR, ALK, BRAF (V600E), MET (exon 14), ROS1, RET, NTRK1/2/3, or BRCA1/2.
15) Known active CNS metastases and/or carcinomatous meningitis. Exceptions:
a) Individuals with asymptomatic untreated brain metastases (that is, no acute neurological symptoms requiring urgent CNS-directed therapy (radiation or surgery), no requirements for corticosteroids, and no lesion >1.5 cm) may participate
b) Individuals with previously treated CNS metastasis may participate provided all of the following are met:
• Any previous local treatment for CNS metastases is completed at least 14 days prior to the first dose of trial treatment
• CNS disease is radiologically stable (i.e., without evidence of progression by repeat imaging for ≥14 days)
• CNS disease is neurologically and clinically stable for ≥14 days prior to the first dose of trial treatment.
o Glucocorticoid therapy (prednisone ≤10 mg daily or equivalent) to treat CNS metastases at time of the start of treatment is allowed
o Prophylactic anticonvulsants are permitted, provided the individual is on a stable dose for ≥14 days prior to the start of treatment, except that individuals taking enzyme-inducing anti-epileptic drugs for CNS metastases must have discontinued such therapy with a washout period equivalent to 5 half-lives of the drug
16) Any unresolved toxicities from prior therapy greater than NCI CTCAE Version 5.0 Grade 1 at the time of starting trial treatment, except for alopecia, peripheral neuropathy and ongoing endocrinopathies controlled on appropriate replacement therapy.
17) Significant cardiovascular disease, defined as any of the following:
a) Unstable angina or acute coronary syndrome within the past 2 months.
b) History of myocardial infarction within 6 months prior to planned start of trial treatment.
c) History of documented LVEF by any method of ≤40% on the most recent trial obtained in the 6 months prior to planned start of trial treatment (screening is not required), unless subsequent measurements (≥2 of any kind, separated by a minimum of 3 weeks) document LVEF recovery to >40%.
d) Grade ≥3 New York Heart Association functional classification system of heart failure, uncontrolled or symptomatic arrhythmias. Chronic and hemodynamically stable atrial arrhythmia well-controlled on medical therapy is permitted.
18) History of noninfectious pneumonitis/ILD that received steroids or has current clinically significant pneumonitis/ILD.
19) Prolongation of the corrected QTcF >470 msec during Screening. If QTcF >470 msec on the ECG obtained during the screening, perform 2 repeat ECGs and average the 3 results to assess eligibility.
• Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
• Correction for underlying BBB allowed.
20) Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the Investigator and the Sponsor, makes it undesirable for the individual to participate in the trial. Screening for chronic conditions is not required.
21) Known active HBV (screening for HBV is not required for individuals who do not have a history of HBV, unless required by local regulations). Individuals with treated/chronic HBV are eligible for the trial provided they meet the following criteria:
a) Individuals with positive HBsAg must be on permitted suppressive antiviral therapy prior to C1D1, remain on the same antiviral treatment throughout trial, and should follow local standards for continuation of therapy after completion of trial therapy.
Note: While HBsAg-negative, anti-hepatitis B core antigen (HBc)–positive individuals are at lower risk of HBV reactivation compared with HBsAg-positive individuals, risk of HBV reactivation should be considered in all individuals and the need for anti-HBV prophylaxis should be carefully assessed prior to the initiation of anticancer therapy.
b) Undetectable HBV DNA ≤14 days of C1D1. Participants who are HBsAg-positive and HBV DNA positive (detectable) will be excluded.
22) Known active HCV (screening for HCV is not required for individuals who do not have a history of HCV unless required by local regulations). Individuals previously treated for HCV are eligible for the trial provided they meet the following criteria:
a) Completion of curative antiviral therapy.
b) HCV viral load below the limit of quantification ≤14 days of C1D1.
c) Negative hepatitis C antibody result OR, if positive, then must be hepatitis C RNA negative.
23) Known untreated HIV infection (screening for HIV is not required unless required by local regulations). Participants on permitted ART and who have well-controlled HIV infection/disease are eligible provided they meet the following criteria:
a) Must be on a stable and permitted ART regimen, without changes in drug or dose, for at least 4 weeks prior to C1D1 and have a viral load of <400 copies per mL prior to ≤14 days of C1D1.
b) CD4+ T-cell count ≥350 cells/uL ≤14 days of C1D1.
24) Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the orally administered trial treatments.
25) Active or history of clinically significant gastrointestinal disease (including but not limited to ulcerative colitis, Crohn's disease, inflammatory bowel disease, immunemediated colitis, peptic ulcer disease, GI bleeding, chronic diarrhea) that in the judgement of the investigator would preclude participation in the trial.
26) Other active malignancy unless in remission with life expectancy >2 years.
27) History of allogenic tissue/solid organ transplant or allogenic stem cell transplant.
Prior/Concomitant Therapy
28) Have received the therapies within the windows specified in the following table (See protocol)
29) Have received a prior KRAS inhibitor targeting any KRAS mutant. With sponsor approval, a limited number of individuals who have received a prior mutant-specific KRAS inhibitor may be allowed to enroll to the monotherapy dose escalation backfill cohorts.
• For individuals that discontinued due to progressive disease, they must have the KRAS mutation detected in a tumor tissue or circulating tumor DNA following progression on the KRAS inhibitor.
• For individuals that discontinued the prior KRAS inhibitor due to toxicity, they must have the KRAS mutation detected in a tumor tissue or circulating DNA within approximately 3 months preceding (or at any time thereafter) discontinuation of the prior KRAS inhibitor.
Other Criteria
30) Have a known hypersensitivity to any component or excipient of any of the trial treatment
31) Part-Specific Criteria (See protocol)
