LY3214996 +/- HCQ in Pancreatic Cancer | NCT04386057

Name	Class
Eli Lilly and Company	INDUSTRY

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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	Drug: Hydroxychloroquine Sulfate Drug: LY3214996
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	Drug: Hydroxychloroquine Sulfate Drug: LY3214996
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	Drug: LY3214996
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

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Hydroxychloroquine Sulfate	Drug	HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle	Cross Over Arm LY3214996 and HCQ Combination

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	28 Months
Dose Limiting Toxicity-Lead In	Dose Limiting Toxicity-Lead In	28 Days

Secondary Outcomes

Measure	Description	Time Frame
Objective Response Rate (ORR)	Objective response rate (ORR) is defined as the number of participants who had a complete or partial response at any time during treatment. 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; Overall Response (OR) = CR + PR.

Eligibility Module

Eligibility Criteria

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 differentiated carcinoma, such as neuroendocrine or acinar cell carcinoma.
Participants who have received a prior MAPK pathway inhibitor, including but not limited to LY3214996.
Participants who have had systemic chemotherapy, other investigational therapy, or immunotherapy within 3 weeks prior to the first dose of study medication.
Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives of the first dose of study medication.
Participants who have received radiation therapy within 2 weeks prior to the first dose of study medication.
Participants who have had major surgery within 4 weeks prior to the first dose of study medication.
Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to LY3214996 or HCQ. Individuals with a history of a different malignancy are ineligible with the following exceptions: individuals who have been treated and are disease-free for a minimum of 3 years prior to study enrollment, or individuals who are deemed by the treating investigator to be at low risk for disease recurrence. Additionally, individuals with the following cancers are eligible if diagnosed and curatively treated within the past 3 years: basal or squamous cell carcinomas of the skin, and breast or cervical carcinomas in situ.
Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant women are excluded from this study because LY3214996 and HCQ are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with LY3214996 or HCQ, breastfeeding should be discontinued if the mother is treated with LY3214996 or HCQ. A negative serum pregnancy test is required for women of childbearing potential prior to the first dose of study medication.
Participants who are known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B or C.
Participants with a history or findings of central or branch retinal artery or venous occlusion with significant vision loss, or other retinal diseases causing visual impairment or would likely cause visual impairment over the time period of the study, as assessed by an ophthalmologist.
Participants with a known personal or family history of long QT syndrome.
Participants with known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Participants who are known at the time of trial enrollment to require concomitant treatment with strong CYP3A4 inhibitors or inducers. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference.

Name	Affiliation	Role
Kimberly Perez, MD	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Massachusetts General Hospital Cancer Center		Boston	Massachusetts	02114	United States
Dana-Farber Cancer Institute

Arm/Group Information

ID	Title	Description
FG000	Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996)	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle. All dose levels will have a 400mg HCQ dose. LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle. Dose level 0 will have a 400mg LY3214996 dose.
FG001	Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996)	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle. All dose levels will have a 400mg HCQ dose. LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle. Dose level -1 will have a 200mg LY3214996 dose.
FG002	LY3214996 and HCQ Combination	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle
FG003	LY3214996-Monotherapy	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 LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle
FG004	Cross Over Arm	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996)	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle. All dose levels will have a 400mg HCQ dose. LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle. Dose level 0 will have a 400mg LY3214996 dose.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Posted

Count of Participants

Participants

28 Months

ID	Title	Description
OG000	Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996)	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle. All dose levels will have a 400mg HCQ dose. LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle. Dose level 0 will have a 400mg LY3214996 dose.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996)	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 Hydroxychloroquine Sulfate: HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle. All dose levels will have a 400mg HCQ dose. LY3214996: LY3214996-daily oral dosage per protocol per 28 day cycle. Dose level 0 will have a 400mg LY3214996 dose.

ID	Term
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004701	Endocrine Gland Neoplasms

ID	Term
D002738	Chloroquine
D000634	Aminoquinolines
D011804	Quinolines
D006574	Heterocyclic Compounds, 2-Ring