Clinical Trials /

LY3214996 and Cetuximab Alone or in Combination With Abemaciclib for the Treatment of Unresectable or Metastatic Colorectal Cancer

NCT04616183

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: LY3214996 and Cetuximab Alone or in Combination With Abemaciclib for the Treatment of Unresectable or Metastatic Colorectal Cancer
  • Official Title: Open-Label Phase 1b/2 Study of Cetuximab Administered in Combination With LY3214996 (ERK 1/2 Inhibitor) or Cetuximab in Combination With LY3214996 and Abemaciclib in Patients With Metastatic, Anti-EGFR-Refractory Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2019-1016
  • SECONDARY ID: NCI-2020-06350
  • SECONDARY ID: 2019-1016
  • SECONDARY ID: R01CA187238
  • NCT ID: NCT04616183

Conditions

  • Metastatic Colon Adenocarcinoma
  • Metastatic Colorectal Carcinoma
  • Metastatic Rectal Adenocarcinoma
  • Recurrent Colorectal Carcinoma
  • Stage III Colon Cancer AJCC v8
  • Stage III Colorectal Cancer AJCC v8
  • Stage III Rectal Cancer AJCC v8
  • Stage IIIA Colon Cancer AJCC v8
  • Stage IIIA Colorectal Cancer AJCC v8
  • Stage IIIA Rectal Cancer AJCC v8
  • Stage IIIB Colon Cancer AJCC v8
  • Stage IIIB Colorectal Cancer AJCC v8
  • Stage IIIB Rectal Cancer AJCC v8
  • Stage IIIC Colon Cancer AJCC v8
  • Stage IIIC Colorectal Cancer AJCC v8
  • Stage IIIC Rectal Cancer AJCC v8
  • Stage IV Colon Cancer AJCC v8
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IV Rectal Cancer AJCC v8
  • Stage IVA Colon Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVA Rectal Cancer AJCC v8
  • Stage IVB Colon Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVB Rectal Cancer AJCC v8
  • Stage IVC Colon Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8
  • Stage IVC Rectal Cancer AJCC v8
  • Unresectable Colon Adenocarcinoma
  • Unresectable Colorectal Carcinoma
  • Unresectable Rectal Adenocarcinoma

Interventions

DrugSynonymsArms
AbemaciclibLY-2835219, LY2835219, VerzenioArm B (ERK1/2 inhibitor LY3214996, cetuximab, abemaciclib)
CetuximabCetuximab Biosimilar CDP-1, Cetuximab Biosimilar CMAB009, Cetuximab Biosimilar KL 140, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225Arm A (ERK1/2 inhibitor LY3214996, cetuximab)
ERK1/2 Inhibitor LY3214996LY 3214996, LY3214996Arm A (ERK1/2 inhibitor LY3214996, cetuximab)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (ERK1/2 inhibitor LY3214996, cetuximab)ExperimentalPatients receive ERK1/2 inhibitor LY3214996 PO QD on days 1-28 and cetuximab IV over 1-2 hours on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cetuximab
  • ERK1/2 Inhibitor LY3214996
Arm B (ERK1/2 inhibitor LY3214996, cetuximab, abemaciclib)ExperimentalPatients receive ERK1/2 inhibitor LY3214996 and cetuximab as in Arm A. Patients also receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Abemaciclib
  • Cetuximab
  • ERK1/2 Inhibitor LY3214996

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of signed Informed Consent prior to any screening procedures being performed

          -  Histologically (or cytologically) confirmed diagnosis of adenocarcinoma of the colon
             or rectum, with clinical confirmation of unresectable and/or metastatic disease that
             is measurable according to RECIST 1.1 criteria

          -  Baseline tissue-based KRAS, NRAS, EGFR, BRAF and MEK1 wild-type tumor

          -  Prior treatment with at least one systemic chemotherapy regimen for mCRC, or
             recurrence/progression with development of unresectable or metastatic disease within 6
             months of adjuvant chemotherapy for resected colorectal cancer

          -  Patients who received chemotherapy must have recovered (Common Terminology Criteria
             for Adverse Events [CTCAE] grade =< 1) from the acute effects of chemotherapy except
             for residual alopecia or grade 2 peripheral neuropathy prior to randomization. A
             washout period of at least 21 days is required between last chemotherapy dose and
             randomization (provided the patient did not receive radiotherapy)

          -  Patients who received radiotherapy must have completed and fully recovered from the
             acute effects of radiotherapy. A washout period of at least 14 days is required
             between end of radiotherapy and randomization

          -  Left-sided primary tumor

          -  Prior treatment with, and progression on, anti-EGFR therapy (cetuximab or panitumumab)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

          -  Hemoglobin (Hgb) >= 9 g/dL with or without transfusions

          -  Platelets (PLT) >= 100 x 10^9/L without transfusions

          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 x upper
             limit of normal (ULN)

          -  Total bilirubin =< 1.5 x ULN and < 2 mg/dL

               -  Note: Patients who have a total bilirubin level > 1.5 x ULN will be allowed if
                  their indirect bilirubin level is =< 1.5 x ULN

          -  Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (determined as per
             Cockcroft-Gault) >= 50 mL/min at screening

          -  Corrected QT (QTc) interval =< 480 ms (preferably the mean from triplicate
             electrocardiograms [ECGs])

          -  Able to take oral medications

          -  Female patients are either postmenopausal for at least 1 year, are surgically sterile
             for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy
             from screening through follow-up if of childbearing potential

               -  Note: Permitted contraception methods include: male condom with spermicide,
                  female condom with spermicide, diaphragm with spermicide, cervical sponge, or
                  cervical cap with spermicide. These should be communicated to the patients 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: Patients 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:

               -  History of acute coronary syndromes (including myocardial infarction, unstable
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
                  months prior to screening

               -  Symptomatic chronic heart failure (i.e. grade 2 or higher), history or current
                  evidence of clinically significant cardiac arrhythmia and/or conduction
                  abnormality < 6 months prior to screening except atrial fibrillation and
                  paroxysmal supraventricular tachycardia

               -  The patient has a personal history of any of the following conditions: syncope of
                  cardiovascular etiology, ventricular arrhythmia of pathological origin
                  (including, but not limited to, ventricular tachycardia and ventricular
                  fibrillation), or sudden cardiac arrest

          -  Uncontrolled hypertension defined as persistent elevation of systolic blood pressure
             >= 150 mmHg or diastolic blood pressure >= 90 mm Hg, despite current therapy

          -  The patient 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
             patient's participation in the clinical study due to safety concerns or compliance
             with clinical study procedures

          -  For patients receiving abemaciclib: The patient 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 < 30 ml/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 human chorionic gonadotropin (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response (complete response [CR] + partial response [PR])
Time Frame:From the start of the treatment until disease progression, assessed up to 1 year
Safety Issue:
Description:Response rate will be calculated based on the number of patients in the evaluable population experiencing a radiographic response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria (either CR or PR) relative to the total number of patients in the efficacy evaluable population. A 95% confidence interval will be estimated around this population.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From enrollment until death, assessed up to 1 year
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate both the survival curves and the median survival time. The 95% confidence intervals for median survival times will also be calculated.
Measure:Progression-free survival (PFS)
Time Frame:From enrollment until death or disease progression as defined by RECIST version 1.1 criteria for the evaluable population, assessed up to 1 year
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the proportion of subjects without progression or death overtime and the median PFS. The 95% confidence intervals for median PFS will also be displayed.
Measure:Incidence of adverse events
Time Frame:Up to 30 days
Safety Issue:
Description:Will be tabulated for adverse events according to Common Terminology Criteria for Adverse Events version 5.0 across all grades.
Measure:pERK and Ki67 inhibition
Time Frame:Up to cycle 1, day 15 (each cycle = 28 days)
Safety Issue:
Description:We will assess reverse phase protein array (RPPA) on tissue biopsies, with dedicated pErk, and RNA sequencing to include gene expression readout of MAPK signature. The loss of pErk positivity and Ki67 inhibition are the major treatment biomarker for MAPK/MEK inhibitors.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

October 30, 2020