LY3214996 +/- HCQ in Pancreatic Cancer

Brief summary public domain (ClinicalTrials.gov)

This study is evaluating the safety and efficacy of combining the study drug LY3214996 with hydroxychloroquine sulfate (HCQ) in patients with advanced pancreatic cancer.

Detailed description public domain (ClinicalTrials.gov)

* This is an open label, randomized, two arm, phase II with safety lead- in study exploring the anti-tumor activity of the extracellular signal-regulated kinase (ERK) inhibitor LY3214996 with and without hydroxychloroquine (HCQ) in patients with advanced pancreatic cancer. * The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. * The safety lead-in will test the safety of a combination of investigational drugs and also try to define appropriate dosage. The names of the study drugs involved in this study are: * LY3214996 * Hydroxychloroquine Sulfate (HCQ) * Following completion of a brief combination treatment safety lead-in cohort, participants will be randomized 1:1 for enrollment to one of two treatment arms: * Arm 1: receiving combination treatment with LY3214996 and HCQ * Arm 2: receiving monotherapy treatment with LY3214996 It is expected that about 52 people will take part in this research study The U.S. Food and Drug Administration (FDA) has not approved LY3214996 as a treatment for any disease. The U.S. Food and Drug Administration (FDA) has not approved HCQ for your specific disease but it has been approved for other uses.

Intervention public domain (ClinicalTrials.gov)

Drug: Hydroxychloroquine Sulfate. HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle

Intervention public domain (ClinicalTrials.gov)

Drug: LY3214996. LY3214996-daily oral dosage per protocol per 28 day cycle

Arm public domain (ClinicalTrials.gov)

Safety Lead-In Cohort (experimental): The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis. Test the safety of study drugs in combination and define dose levels. * LY3214996 * HCQ

Arm public domain (ClinicalTrials.gov)

LY3214996 and HCQ Combination (experimental): The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days. Treatment will be administered on an outpatient basis. Combined dosage per determined Lead-In Cohort * LY3214996 * HCQ

Arm public domain (ClinicalTrials.gov)

LY3214996-Monotherapy (experimental): The research study procedures include screening for eligibility and study treatment. Study treatment will include evaluations, biopsies, and follow up visits. A treatment cycle will be defined as 28 consecutive days.Treatment will be administered on an outpatient basis. -LY3214996

Arm public domain (ClinicalTrials.gov)

Cross Over Arm (experimental): Participants who are enrolled to Arm 2 who experience radiologic disease progression on monotherapy will have the option to cross-over to receive treatment with the combination. Crossover will occur at the treating investigator's discretion following consultation and approval from the overall principal investigator. Combined dosage per determined Lead-In Cohort * LY3214996 * HCQ

Primary outcome public domain (ClinicalTrials.gov)

Disease Control Rate (DCR). Anti-tumor activity will be measured via disease control rate (DCR), which will be defined as the proportion of patients with complete response (CR), partial response (PR) or stable disease (SD) that persists for ≥ 4 months. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the diameters of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Time frame: 28 Months.

Primary outcome public domain (ClinicalTrials.gov)

Dose Limiting Toxicity-Lead In. Dose Limiting Toxicity-Lead In Time frame: 28 Days.

Secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR). Time frame: 28 Months.

Secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS). Time frame: time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation up to 28 Months.

Secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS). Time frame: Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. OS was calculated for a median of 115 days, ranging from 18 - 327 days..

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: * Participants must have histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the pancreas. * Age ≥ 18 years. * ECOG performance status ≤ 1 * Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam. * Participants must have received at least one but no more than two prior lines of systemic therapy for metastatic pancreatic cancer. Perioperative treatment (chemotherapy and/or radiation) is not considered a prior line of therapy. * Participants must have adequate organ and marrow function as defined below: * Absolute Neutrophil Count ≥ 1,500/mcL * Platelet Count ≥ 100,000/mcL * Total Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) * AST (SGOT) / ALT(SGPT) ≤ 2.5 × institutional ULN, OR * AST (SGOT) / ALT (SGPT) ≤ 5 × institutional ULN if elevation is a result of metastases * Creatinine ≤ 1.5 × institutional ULN, OR * Creatinine Clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above 1.5 × institutional normal (calculated via the Cockcroft-Gault equation) * The effects of LY3214996 or HCQ on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of LY3214996 or HCQ administration. * Ability to understand and the willingness to sign a written informed consent document. * Ability to swallow and retain oral medication * Baseline QTcB of ≤ 470 msec on screening EKG. * Participants must be able and willing to undergo the pre-treatment biopsy procedure, and have a cancer site amenable to biopsy. Exclusion Criteria: * Participants with pancreatic histologies other than adenocarcinoma or poorly …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 52 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Disease Control Rate (DCR) [28 Months]. Count Of Participants, Participants. Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) (n=7): 0; Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) (n=6): 1; LY3214996 and HCQ Combination (n=20): 1; LY3214996-Monotherapy (n=16): 1; Cross Over Arm (n=3): 0.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Dose Limiting Toxicity-Lead In [28 Days]. Count Of Participants, Participants. Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) (n=7): 2; Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) (n=6): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR) [28 Months]. Count Of Participants, Participants. Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) (n=7): 0; Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) (n=6): 0; LY3214996 and HCQ Combination (n=20): 1; LY3214996-Monotherapy (n=16): 0; Cross Over Arm (n=3): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS) [time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation up to 28 Months]. Median, months (95% Confidence Interval). LY3214996 and HCQ Combination (n=14): 1.3 (0.8 to 1.8); LY3214996-Monotherapy (n=17): 1.9 (1.6 to 2.4).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival (OS) [Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. OS was calculated for a median of 115 days, ranging from 18 - 327 days.]. Median, months (95% Confidence Interval). LY3214996 and HCQ Combination (n=17): 2.4 (1.3 to 5.8); LY3214996-Monotherapy (n=19): 4.7 (3.1 to 5.7).