Neoplasm Metastasis, Colorectal Neoplasms, Breast Cancer
Conditions
Keywords
cancer
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.
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.
Interventions
DRUGG-CSF
Administered SC
DRUGPemetrexed
Administered IV
DRUGFluorouracil
Administered IV
DRUGLY3023414
Administered PO
DRUGLeucovorin
Administered IV
DRUGPrexasertib
Administered IV
DRUGCisplatin
Administered IV
DRUGCetuximab
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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: Maximum Plasma Concentration of Prexasertib | Cycle 1 Predose through Cycle 2, Day 15 |
| 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 |
| Pharmacokinetics: Area Under the Plasma Concentration Curve of LY3023414 | Time Frame: Cycle 1 Predose through Cycle 2, Day 2 |
| 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 |
Countries
United States
Outcome results
None listed