Pancreatic Cancer, Advanced Cancer
Conditions
Keywords
Pancreatic Cancer, Advanced Cancer, Extracellular Signal-Regulated Kinases, Cell Growth Inhibitors
Brief summary
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
* 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.
Interventions
DRUGHydroxychloroquine Sulfate
HCQ will be administered by mouth twice daily continuously throughout each treatment per 28 day cycle
DRUGLY3214996
LY3214996-daily oral dosage per protocol per 28 day cycle
Sponsors
Eli Lilly and Company
Kimberly Perez, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 28 Months | 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. |
| Dose Limiting Toxicity-Lead In | 28 Days | Dose Limiting Toxicity-Lead In |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 28 Months | 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. |
| 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 | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study . The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesion and/or unequivocal progression of existing non-target lesions are also considered progression. Unequivocal progression should not normally trump target lesion status and must be representative of overall disease status change, not a single lesion increase. |
| 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. | Kaplan and Meier to assess Overall survival (OS) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 7 |
| 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. | 6 |
| 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 | 20 |
| 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 | 16 |
| 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 | 3 |
| Total | 52 |
Baseline characteristics
| Characteristic | Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | LY3214996 and HCQ Combination | LY3214996-Monotherapy | Cross Over Arm | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 4 Participants | 10 Participants | 13 Participants | 3 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 10 Participants | 3 Participants | 0 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 17 Participants | 16 Participants | 2 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 5 Participants | 17 Participants | 14 Participants | 3 Participants | 43 Participants |
| Region of Enrollment United States | 7 participants | 6 participants | 20 participants | 16 participants | 3 participants | 52 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 7 Participants | 6 Participants | 1 Participants | 19 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 13 Participants | 10 Participants | 2 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 7 | 6 / 6 | 18 / 20 | 13 / 16 | 3 / 3 |
| other Total, other adverse events | 7 / 7 | 6 / 6 | 16 / 20 | 16 / 16 | 3 / 3 |
| serious Total, serious adverse events | 7 / 7 | 3 / 6 | 6 / 20 | 4 / 16 | 1 / 3 |
Outcome results
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.
Time frame: 28 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Disease Control Rate (DCR) | 0 Participants |
| Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | Disease Control Rate (DCR) | 1 Participants |
| LY3214996 and HCQ Combination | Disease Control Rate (DCR) | 1 Participants |
| LY3214996-Monotherapy | Disease Control Rate (DCR) | 1 Participants |
| Cross Over Arm | Disease Control Rate (DCR) | 0 Participants |
Primary
Dose Limiting Toxicity-Lead In
Dose Limiting Toxicity-Lead In
Time frame: 28 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Dose Limiting Toxicity-Lead In | 2 Participants |
| Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | Dose Limiting Toxicity-Lead In | 0 Participants |
Secondary
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.
Time frame: 28 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Objective Response Rate (ORR) | 0 Participants |
| Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | Objective Response Rate (ORR) | 0 Participants |
| LY3214996 and HCQ Combination | Objective Response Rate (ORR) | 1 Participants |
| LY3214996-Monotherapy | Objective Response Rate (ORR) | 0 Participants |
| Cross Over Arm | Objective Response Rate (ORR) | 0 Participants |
Secondary
Overall Survival (OS)
Kaplan and Meier to assess 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.
Population: OS (months) was calculated for participants only in the randomized arms (including crossovers in their original arm) as an Intention to Treat Analysis (ITT). Analyses were not completed for participants in the safety lead-in cohort, as this cohort was intended to evaluate safety only; not efficacy. Only 17 participants were evaluable from Arm A and 19 were evaluable from Arm B. These numbers differ slightly to the overall number of participants due to missing data and adding crossovers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Overall Survival (OS) | 2.4 months |
| Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | Overall Survival (OS) | 4.7 months |
Secondary
Progression-free Survival (PFS)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study . The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesion and/or unequivocal progression of existing non-target lesions are also considered progression. Unequivocal progression should not normally trump target lesion status and must be representative of overall disease status change, not a single lesion increase.
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
Population: PFS (months) was calculated for participants only in the randomized arms (including crossovers in their original arm) as an Intention to Treat Analysis (ITT). Analyses were not completed for participants in the safety lead-in cohort, as this cohort was intended to evaluate safety only; not efficacy. Only 14 participants were evaluable for PFS in Arm A and 17 were evaluable in Arm B. These numbers differ slightly to the overall number of participants due to missing data and adding crossovers.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Safety Lead-In Cohort: Dose Level 0 (400mg LY3214996) | Progression-free Survival (PFS) | 1.3 months |
| Safety Lead-In Cohort: Dose Level -1 (200mg LY3214996) | Progression-free Survival (PFS) | 1.9 months |