IRB Study Number 24-835
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the safety and tolerability of LY3962673 monotherapy
Dose Expansion: To assess the antitumor activity of LY3962673
Dose Optimization: To confirm the RP2D/optimal dose based on safety and efficacy of LY3962673
Secondary Objectives
To assess the antitumor activity of LY3962673 monotherapy
To characterize the PK properties of LY3962673 monotherapy
Dose Expansion: To assess the safety and tolerability of LY3962673
Dose Expansion: To assess, for each Dose Expansion cohort, the antitumor activity per RECIST v1.1
All Cohorts: To characterize the PK properties of LY3962673
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) Histological or cytologically proven diagnosis of locally advanced, unresectable, and/or metastatic cancer and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
3) Have evidence of KRAS G12D mutation in tumor tissue or circulating tumor DNA as determined by molecular testing performed at a Clinical Laboratory Improvement Amendments (CLIA), International Organization for Standardization/ International Electrotechnical Commission (ISO/IEC), College of American Pathologists (CAP), or other similar certified laboratory as per local guidelines including, but not limited to, In Vitro Diagnostic Regulation (European Union) 2017/746 (IVDR) compliance as applicable.
4) Phase 1a (Part A): Must have received ≥ 1 prior line of systemic therapy.
a) A limited number of individuals who have progressed on a prior KRAS inhibitor are allowed to enroll with Sponsor approval. These individuals must have KRAS G12D mutation detected in a tumor tissue or circulating tumor DNA within approximately 3 months preceding (or at any time thereafter) discontinuation of prior KRAS inhibitor due to disease progression.
b) Individuals who have discontinued a prior KRAS inhibitor due to prior toxicity are eligible only for backfill in dose escalation with Sponsor approval and not for initial safety evaluation.
5) Phase 1b disease-specific criteria:
Parts B and C:
• Individuals should only be enrolled if, in the Investigator’s judgment, the individual is an appropriate candidate to initiate the planned treatment regimen at the dose levels specified in Table 9. If a dose modification is required or DLT-equivalent toxicity is observed in a treatment course prior to enrollment, the individual is not eligible.
• Individuals are considered treatment naïve if their prior therapy was:
• The same regimen/doses as specified in the cohort they are enrolling in.
• Initiated within 28 days prior to the start of trial treatment.
a) Part B – PDAC:
i) Histologically or cytologically confirmed KRAS G12D-mutant PDAC.
ii) Cohort B1: Must have received ≥ 1 prior line of systemic chemotherapy for advanced or metastatic PDAC.
iii) Cohorts B2, B3, and B4: Individuals may be treatment naïve for advanced or metastatic PDAC.
iv) Cohort B5: Individuals must be treatment naïve for advanced or metastatic PDAC.
b) Part C – CRC
i) Histologically or cytologically confirmed KRAS G12D-mutant CRC.
ii) Cohorts C1 and C2: Must have received ≥ 1 prior fluoropyrimidine-based therapy for CRC.
iii) Cohorts C3, C4, and Cohort C5: Individuals may be treatment naïve for advanced or metastatic CRC.
c) Part D – NSCLC
i) Histologically or cytologically confirmed KRAS G12D-mutant NSCLC.
ii) Must have received ≥ 1 prior line(s) of therapy for advanced or metastatic NSCLC.
d) Part E – Other Solid Tumors
i) Histologically or cytologically confirmed KRAS G12D-mutant advanced or metastatic solid tumor other than PDAC, CRC, or NSCLC.
ii) Must have received ≥ 1 prior line(s) of systemic therapy for advanced or metastatic disease.
6) Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
7) Must have adequate organ function as defined in the following table: (See protocol)
Contraception
8) Women of childbearing potential (WOCBP) (defined as not postmenopausal for at least 2 years or not surgically sterile) 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.
Highly effective methods of birth control are:
a) Total abstinence from intercourse; periodic abstinence is not acceptable. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual.
b) Surgical sterilization as appropriate by vasectomy, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
c) Intrauterine device.
d) Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal); the specific contraceptive must have been used for at least 3 months prior to trial intervention administration. Hormonal contraceptives must be associated with inhibition of ovulation and must be used with a barrier method of contraception.
9) WOCBP must have a negative serum pregnancy test documented within 14 days prior to initiation of treatment and a negative urine or serum pregnancy test obtained on Cycle 1 Day 1 (C1D1) if the serum pregnancy test was obtained more than 7 days prior to C1D1.
Informed Consent
10) 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 informed consent form (ICF) and in this protocol.
Other Criteria
11) Must be able to swallow tablets.
12) Must be able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of trial participation.
Exclusion Criteria
Medical Conditions
13) Known actionable tumor-specific co-occurring driver alteration such as but not limited to EGFR, ALK, BRAF (V600E), MET (exon 14), ROS1, RET, or NTRK1/2/3. Participants with other activating KRAS mutations (e.g., G12V, G12C) are excluded, although for participants previously treated with a RAS inhibitor, certain co-occurring KRAS mutations may be allowed with Sponsor approval.
14) Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Individuals with previously treated CNS metastases may participate provided:
a) The individual has completed prior CNS-directed therapy (including radiation and/or surgery) ≥ 14 days prior to the first dose of trial treatment.
b) CNS disease is neurologically and radiologically stable (i.e., without evidence of progression by repeat imaging) for ≥ 14 days prior to the first dose of trial treatment by repeat imaging (imaging should be performed during trial screening).
c) Glucocorticoid therapy (prednisone ≤ 10 mg daily or equivalent) at time of the start of treatment will be allowed in individuals that are neurologically stable.
d) Prophylactic anticonvulsants are permitted, provided the individual is on a stable dose for ≥ 14 days prior to enrollment, except individuals taking enzyme-inducing anti-epileptic drugs must have discontinued such therapy with a washout period equivalent to 5 half-lives of the drug.
e) Participants 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.
15) Any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (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.
16) 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) Known left ventricular ejection fraction (LVEF) by any method of ≤ 40% in the 6 months prior to planned start of trial treatment, unless subsequent measurements (≥ 2 of any kind, separated by a minimum of 3 weeks) document LVEF recovery to > 40%. Screening echocardiogram (ECG) is not required.
d) Grade ≥ 3 New York Heart Association functional classification system of heart failure or uncontrolled or symptomatic arrhythmias. Chronic and hemodynamically stable atrial arrhythmia well-controlled on medical therapy is permitted.
17) Prolongation of the corrected QT interval by Fridericia (QTcF) > 470 msec during Screening. QTcF is calculated using Fridericia’s Formula: QTcF = QT/(RR0.33). If QTcF > 470 msec on the ECG obtained during the Screening, perform 2 repeat ECGs and average the 3 results to assess eligibility.
• Note: 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 bundle branch block (BBB) is allowed. 18) 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.
19) 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 hepatitis B surface antigen (HBsAg) must be on permitted suppressive antiviral therapy (see Section 6.8.1 for restricted concomitant therapies) 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, antihepatitis B core antigen (HBcAg)–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 28 days of C1D1.
Note: Participants who are HBsAg-positive and HBV DNA positive (detectable) will be excluded.
20) 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 28 days of C1D1.
c) Negative hepatitis C antibody result or, if positive, then must be hepatitis C RNA negative.
21) Known untreated HIV infection (screening for HIV is not required unless required by local regulations). Participants on permitted antiretroviral therapy (ART) and who have wellcontrolled HIV infection/disease are eligible provided they meet the following criteria:
a) Must be on a stable and permitted ART regimen (see Section 6.8.1 for restricted concomitant therapies), without changes in drug or dose, for at least 4 weeks prior to C1D1 and have a viral load of <400 copies per mL 28 days of C1D1.
b) CD4+ T-cell count 350 cells/uL 28 days of C1D1.
22) Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the oral administered trial treatments.
23) Other active malignancy unless in remission with life expectancy > 2 years.
24) Individuals with known low or absent dihydropyrimidine dehydrogenase activity may not participate in cohorts administering 5-FU: Cohorts B4, B5, C3, C4, or C5. Screening is not required.
Prior/Concomitant Therapy
25) Individuals who have received the therapies within the windows specified in the following table are excluded: (See protocol)
26) Prior KRAS inhibitor except as allowed in Phase 1a according to Inclusion Criterion 4 (may allow limited number per DL).
Other Criteria
27) Pregnant and/or planning to breastfeed during the trial or within 180 days of the last dose of trial intervention.
28) Individual has a known allergic reaction to or hypersensitivity to any component of the trial treatments.
