A Study of Prexasertib (LY2606368) With Chemotherapy or Targeted Agents in Participants With Advanced Cancer

Sponsor

Eli Lilly and Company (Industry)

Overall Status

Completed

CT.gov ID

NCT02124148

Collaborator

(none)

167

Enrollment

Locations

Arms

67.9

Actual Duration (Months)

33.4

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main purpose of this study is to investigate the safety of prexasertib in combination with other anti-cancer drugs (cisplatin, cetuximab, pemetrexed, fluorouracil or LY3023414) in participants with advanced cancer or cancer that has spread to another part of the body. The study has multiple parts (A, B, C, D and E). Participants will only enroll in one part.

Condition or Disease	Intervention/Treatment	Phase
Neoplasm Metastasis Colorectal Neoplasms Breast Cancer	Drug: Prexasertib Drug: Cisplatin Drug: Cetuximab Drug: G-CSF Drug: Pemetrexed Drug: Fluorouracil Drug: LY3023414 Drug: Leucovorin	Phase 1

Detailed Description

The primary purpose of Parts A, B, C, D and E of this study is to determine a recommended dose level and schedule of prexasertib (an inhibitor of checkpoint kinase 1 and 2 [CHK1/CHK2] in combination with:

cisplatin (Part A)
cetuximab (Part B)
pemetrexed (Part C)
fluorouracil (Part D)
LY3023414 (Part E) [An inhibitor of phosphoinositide 3-kinase alpha (PI3K alpha) and mammalian target of rapamycin (mTOR), DNA-dependent protein kinase (DNA-PK), and other class I phosphoinositide 3-kinase (PI3K) family members]

in participants with advanced or metastatic cancer.

Part A dose expansion of the study will evaluate the safety and toxicity of prexasertib at the recommended dose level in combination with cisplatin in participants with advanced or metastatic cancer, Part B dose expansion of the study will evaluate the safety and toxicity of prexasertib at the recommended dose level in combination with cetuximab in participants with advanced or metastatic colorectal cancer, Part C and D dose expansions have been removed and Part E dose expansion of the study will evaluate the safety and toxicity of prexasertib at the recommended dose level in combination with LY3023414 in participants with advanced or metastatic cancer, participants with PIK3CA mutations, or with advanced or metastatic breast cancer.

In Parts A and B the effect of adding granulocyte colony stimulating factor (G-CSF) to cisplatin in combination with prexasertib and cetuximab in combination with prexasertib will be explored. In Part A the effect of changing the schedule of prexasertib and cisplatin also will be explored. In Part B the effect of changing the schedule of prexasertib and cetuximab also will be explored.

Study Design

Study Type:

Interventional

Actual Enrollment :

167 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b Trial of LY2606368 in Combination With Chemotherapy or Targeted Agents in Advanced and/or Metastatic Tumors

Actual Study Start Date :

Jun 18, 2014

Actual Primary Completion Date :

Feb 13, 2020

Actual Study Completion Date :

Feb 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prexasertib + Cisplatin (Part A) Part A: Prexasertib and cisplatin administered intravenously (IV) once every 21 days. Part A2: Prexasertib and cisplatin administered IV every 21 days; G-CSF administered subcutaneously (SC) starting approximately 24 hours after each prexasertib dose every 21 days. Part A3: Cisplatin administered IV on day one and prexasertib administered IV on day two once every 21 days. Part A Expansion: Part A, A2, and/or A3 may be expanded at the recommended dose. Participants may remain on treatment until discontinuation criteria are met.	Drug: Prexasertib Administered IV Other Names: LY2606368 Drug: Cisplatin Administered IV Drug: G-CSF Administered SC
Experimental: Prexasertib + Cetuximab (Part B) Part B: Cetuximab administered IV weekly and prexasertib administered IV once every 14 days. Part B2: Cetuximab administered IV weekly and prexasertib administered IV once every 14 days; G-CSF administered SC starting approximately 24 hours after each prexasertib dose every 14 days. Part B3: Cetuximab administered IV with prexasertib administered IV once every 14 days. Part B Expansion: Part B, B2 and/or B3 may be expanded at the recommended dose. Participants may remain on treatment until discontinuation criteria are met.	Drug: Prexasertib Administered IV Other Names: LY2606368 Drug: Cetuximab Administered IV Other Names: Erbitux Drug: G-CSF Administered SC
Experimental: Prexasertib + Pemetrexed (Part C) Part C: Pemetrexed administered IV on day one and prexasertib administered IV on day one and two every 21 days. Participants may remain on treatment until discontinuation criteria are met.	Drug: Prexasertib Administered IV Other Names: LY2606368 Drug: Pemetrexed Administered IV Other Names: Alimta
Experimental: Prexasertib + 5-FU (Part D) Part D: Leucovorin administered IV on day one, 5-FU administered IV bolus on day one and by continuous IV on days one to three (46 hours), and prexasertib administered IV on day three every 14 days. Participants may remain on treatment until discontinuation criteria are met.	Drug: Prexasertib Administered IV Other Names: LY2606368 Drug: Fluorouracil Administered IV Drug: Leucovorin Administered IV
Experimental: Prexasertib + LY3023414 (Part E) Part E: Prexasertib administered IV on day one and LY3023414 administered orally twice daily every 14 days. Part E will be expanded at the recommended dose in participants with advanced or metastatic cancer, participants with PIK3CA mutations (E2 expansion), or with advanced or metastatic ER-negative, PR-negative, and HER-2 non-overexpressing breast cancer (E3 expansion). Participants may remain on treatment until discontinuation criteria are met.	Drug: Prexasertib Administered IV Other Names: LY2606368 Drug: LY3023414 Administered PO

Outcome Measures

Primary Outcome Measures

Part A: Maximum Tolerated Dose and Schedule of Prexasertib in Combination with Cisplatin [Cycle 1 predose through last dose last cycle (estimated up to 24 weeks)]
Part B: Maximum Tolerated Dose of Prexasertib in Combination with Cetuximab [Cycle 1 predose through last dose last cycle (estimated up to 24 weeks)]
Part C: Maximum Tolerated Dose of Prexasertib in Combination with Pemetrexed [Cycle 1 predose through last dose last cycle (estimated up to 24 weeks)]
Part D: Maximum Tolerated Dose of Prexasertib in Combination with Fluorouracil (5-FU) [Cycle 1 predose through last dose last cycle (estimated up to 24 weeks)]
Part E: Maximum Tolerated Dose of Prexasertib in Combination with LY3023414 [Cycle 1 predose through last dose last cycle (estimated up to 24 weeks)]

Secondary Outcome Measures

Pharmacokinetics: Maximum Plasma Concentration of Prexasertib [Cycle 1 Predose through Cycle 2, Day 15]
Pharmacokinetics: Area Under the Plasma Concentration Curve of Prexasertib [Cycle 1 Predose through Cycle 2, Day 15]
Pharmacokinetics: Maximum Plasma Concentration of Cisplatin (Total Platinum) [Cycle 1 Predose through Cycle 2, Day 1]
Pharmacokinetics: Area Under the Plasma Concentration Curve of Cisplatin (Total Platinum) [Cycle 1 Predose through Cycle 2, Day 1]
Pharmacokinetics: Maximum Plasma Concentration of Cetuximab [Cycle 1 Predose through Cycle 3, Day 1]
Pharmacokinetics: Maximum Plasma Concentration of Pemetrexed [Cycle 1 Predose through Cycle 1, Day 2]
Pharmacokinetics: Area Under the Plasma Concentration Curve of Pemetrexed [Cycle 1 Predose through Cycle 1, Day 2]
Pharmacokinetics: Maximum Plasma Concentration of 5-FU [Cycle 1 Predose through Cycle 1, Day 3]
Pharmacokinetics: Maximum Plasma Concentration of LY3023414 [Cycle 1 Predose through Cycle 2, Day 2]
Pharmacokinetics: Area Under the Plasma Concentration Curve of LY3023414 [Time Frame: Cycle 1 Predose through Cycle 2, Day 2]
B2, E2, E3 Dose Expansion: Overall Response Rate [Baseline through disease progression (estimated as up to 24 weeks) or death from any cause]
B2, E2, E3 Dose Expansion: Disease Control Rate [Baseline through disease progression (estimated as up to 24 weeks) or death from any cause]
B2, E2, E3 Dose Expansion: Progression-Free Survival [Baseline through disease progression (estimated as up to 24 weeks) or death from any cause]
B2, E2, E3 Dose Expansion: Duration of Response [Baseline through disease progression (estimated as up to 24 weeks) or death from any cause]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must be appropriate candidate for experimental therapy, as determined by investigator, after available standard therapies have failed
Have adequate organ function
Prior Therapies: Systemic treatments: must have discontinued previous systemic treatments for cancer and recovered from the acute effects of therapy. Participants must have discontinued mitomycin-C or nitrosourea therapy at least 42 days and have discontinued any cytotoxic therapies at least 28 days prior to study enrollment. Radiation therapy and surgery: must be completed at least 4 weeks before study enrollment
All parts except Part B, Part E2, and Part E3 dose expansion: Must have diagnosis of cancer that is advanced or metastatic
Part B dose expansion: Must have confirmed Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type colorectal cancer that is metastatic or recurrent and has failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant of irinotecan or oxaliplatin
Part E2 dose expansion: must have cancer that is advanced or metastatic and have prior documentation of a mutation of PIK3CA
Part E3 dose expansion: must have advanced or metastatic ER-negative, PR-negative, and HER-2 non-overexpressing breast cancer
Must be available during the duration of the study and willing to follow the study procedures
Parts A and B: If participant is of reproductive potential, must agree to use medically approved contraceptive precautions during the study and for six months following the last dose of study drug
Parts C, D and E: If participant is of reproductive potential, must agree to use medically approved contraceptive precautions during the study and for three months following the last dose of study drug
If the participant is a female of childbearing potential, must have had a negative serum or urine pregnancy test within 14 days of the first dose of study drug and must not be breast feeding
Part E: Are able to swallow capsules or tablets

Exclusion Criteria:

Have received more than 2 previous lines of cytotoxic chemotherapy (if receiving cisplatin, 5-FU or pemetrexed)
Must not have taken an unapproved drug as treatment for any indication within the last 28 days prior to starting study treatment
Must not have an active symptomatic fungal, bacterial or viral infection, including human immunodeficiency virus (HIV) or Hepatitis A, B, or C
Must not have a serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last three months
Must not have a family history of long QTc syndrome
Must not have a serotonin-secreting carcinoid tumor or a prior history of drug-induced serotonin syndrome
Must not have acute leukemia
Part E: Have insulin-dependent (type I) diabetes or a history of gestational diabetes
Part E: Prior treatment with a PI3K/mTOR inhibitor

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Sarasota	Florida	United States	34232
2	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
3	Sarah Cannon Research Institute SCRI	Nashville	Tennessee	United States	37203
4	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
5	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

Eli Lilly and Company

Investigators

Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company