Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This phase Ib/II trial investigates the side effects and best dose of LY3214996 when given together with cetuximab alone or in combination with abemaciclib and to see how well they work in treating patients with colorectal cancer that cannot be removed by surgery (unresectable) and/or has spread to other places in the body (metastatic). Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. LY3214996 and abemaciclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving LY3214996 and cetuximab alone or in combination with abemaciclib may help treat patients with colorectal cancer.
Full description
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ERK1/2 inhibitor LY3214996 (LY3214996) administered in combination with cetuximab. (Phase 1b) II. Determine the MTD and RP2D of LY3214996 administered in combination with cetuximab plus abemaciclib. (Phase 1b) III. Assess the preliminary antitumor activity of the treatment combinations based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (Phase 2)
SECONDARY OBJECTIVES:
I. Assess the preliminary antitumor activity of the treatment combinations based on RECIST v.1.1. (Phase 1b) II. Characterize the safety profile of the treatment combinations (DLTs). III. Evaluate for pERK and Ki67 inhibition.
EXPLORATORY OBJECTIVES:
I. Assess blood- and tissue-based predictive biomarkers of activity and immune effects upon treatment with cetuximab, LY3214996, and abemaciclib.
II. Demonstrate feasibility of establishing patient-derived xenograft (PDX) models in matched patients with cetuximab-refractory metastatic colorectal cancer (mCRC) to evaluate for biomarkers of response and mechanisms of resistance.
III. Explore mechanisms of resistance to cetuximab plus LY3214996 and cetuximab, LY3214996, plus abemaciclib.
OUTLINE: This is a phase Ib, dose-escalation study of ERK1/2 inhibitor LY3214996 followed by a phase II study. Patients are assigned to 1 of 2 arms.
ARM A: Patients receive ERK1/2 inhibitor LY3214996 orally (PO) once daily (QD) on days 1-28 and cetuximab intravenously (IV) over 1-2 hours on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive ERK1/2 inhibitor LY3214996 and cetuximab as in Arm A. Patients also receive abemaciclib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Note: Permitted contraception methods include: male condom with spermicide, female condom with spermicide, diaphragm with spermicide, cervical sponge, or cervical cap with spermicide. Also see the definition of highly effective method of contraception in Appendix 1. These should be communicated to the participants and their understanding confirmed. For all females, the pregnancy test result must be negative within 24 hours of starting treatment on study and within 24 hours prior to each cycle. Males must agree to take appropriate precautions to avoid fathering a child from screening through 100 days following the end of therapy.
Exclusion criteria
History of a Grade 3 or 4 allergic reaction or intolerability attributed to cetuximab.
Right-sided or transverse colonic primary tumor.
Baseline tissue-based KRAS, NRAS, EGFR, BRAF and MEK1 mutated tumor
Active infection requiring concurrent antibiotic use.
Currently using concomitant medications that are strong inhibitors or inducers of CYP3A4.
Previously completed or withdrawn from this study or any other study investigating an ERK1/2 inhibitor.
Any known symptomatic brain metastasis. Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Known brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.
Known leptomeningeal disease
Previous or concurrent malignancy within 3 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; other solid tumors treated curatively without evidence of recurrence for at least 3 years prior to study entry.
Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 90 mm Hg, despite current therapy;
The participant has active systemic bacterial infection (requiring intravenous (IV) antibiotics at time of initiating study treatment,) fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C (for example, hepatitis B surface antigen positive.) Screening is not required for enrollment.; Known history of acute or chronic pancreatitis (history of acute pancreatitis with no recurrent events in the prior 24 months are permitted)
Impaired gastrointestinal function or disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
Any other condition that would, in the Investigator's judgment, contraindicate the participants participation in the clinical study due to safety concerns or compliance with clinical study procedures.
For participants receiving abemaciclib: The participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
Major surgery ≤ 6 weeks prior to starting study drug or failure to recover from side effects of such procedure at the discretion of the treating investigator.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study.
Primary purpose
Allocation
Interventional model
Masking
46 participants in 2 patient groups
Loading...
Central trial contact
Christine M Parseghian
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal