Clinical Trials /

Panitumumab With or Without Trametinib in Treating Patients With Stage IV Colorectal Cancer

NCT03087071

Description:

This phase II clinical trial studies how well panitumumab with or without trametinib works in treating patients with stage IV colorectal cancer. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panitumumab with or without trametinib may work better in treating patients with stage IV colorectal cancer.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Panitumumab in Combination With Trametinib in Cetuximab-Refractory Stage IV Colorectal Cancer
  • Official Title: A Phase II Enrichment Study of Panitumumab as a Single Agent or in Combination With Trametinib in Cetuximab-Refractory Stage IV Colorectal Cancer Patients

Clinical Trial IDs

  • ORG STUDY ID: 2016-0338
  • NCT ID: NCT03087071

Conditions

  • Colorectal Cancer

Interventions

DrugSynonymsArms
PanitumumabVectibixCohort 1
TrametinibGSK1120212Cohort 2

Purpose

The goal of this clinical research study is to learn if panitumumab alone or in combination with trametinib can help to control advanced colorectal cancer. The safety of these drugs will also be studied.

Detailed Description

Study Groups:

If participant is found to be eligible to take part in this study, participant will be assigned to 1 of 3 groups based on the results of the genetic testing done at screening.

- If participant is in Group 1 or 3, participant will receive panitumumab alone.

- If participant is in Group 2, participant will receive will receive panitumumab and trametinib.

If participant is in Group 1 or 3 and the disease appears to get worse, participant may be able to cross-over to group 2 and begin to receive the panitumumab and trametinib combination therapy.

Study Drug Administration:

Each study cycle is 14 days.

Participant will receive panitumumab by vein over about 60-90 minutes on Day 1 of each cycle. After the first dose, participant will be checked for side effects for about 60 minutes after the dose. If no intolerable side effects occur, participant's next dose will last about 30 minutes and participant will be checked for side effects for 30 minutes afterward.

If participant is in Group 2, participant will take trametinib by mouth 1 time every day.

Participant should take the trametinib tablets in the morning at about the same time each day, at least 1 hour before or 2 hours after a meal. Participant should swallow the capsules with about 1 cup (8 ounces) of water. Participant should swallow each capsule whole (without chewing), one right after the other.

At the end of each study cycle or if participant stops taking the study drug, participant should return any unused trametinib capsules to the study nurse.

Length of Study:

Participant may continue receiving the study drug(s) for as long as the doctor thinks it is in participant's best interest. Participant will no longer be able to receive the study drug(s) if the disease gets worse, if intolerable side effects occur, or if participant is unable to follow study directions.

Study Visits:

On Day 1 of every cycle:

- Blood (about 6 tablespoons) will be drawn for routine and biomarker testing.

- If the doctor thinks it is needed, participant will have an eye exam.

- Participant will have a physical exam (Cycles 1-4, and every even-numbered cycle after that)

- Participant will have an EKG (Cycles 1-4, and every even-numbered cycle after that).

- Participant will have either an ECHO or MUGA scan (Cycles 2, 4, and 10, and then every 6 cycles after that)

On Day 10 of Cycle 2, if the doctor thinks it is needed, participant will have an eye exam.

On Day 10 of Cycle 4 and every 4 cycles after that (Cycles 8, 12, 16, and so on):

- Participant will have a CT of participant's chest and CT/MRI of participant's abdomen and pelvis.

- If the doctor thinks it is needed, participant will have an eye exam.

End of Treatment Visit:

Within 28-35 days after participant's last dose of study drug, participant will have an end-of-treatment visit. The following tests and procedures will be performed:

- Participant will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine and biomarker testing.

- Participant will have an EKG and either an ECHO or MUGA scan.

- Participant will have a CT scan of participant's chest and a CT scan or MRI of participant's abdomen and pelvis.

- If the doctor thinks it is needed, participant will have an eye exam.

- If participant can become pregnant, blood (about 1 teaspoon) will be collected for a pregnancy test.

Long-Term Follow-Up:

Every 3 months after the end of treatment visit, a member of the study staff will contact participant to ask how participant is doing. This contact will take place either during a regularly scheduled clinic visit or by phone. Each phone call should last about 10 minutes.

This is an investigational study. Panitumumab is FDA approved and commercially available for the treatment of colorectal cancer. Trametinib is FDA approved and commercially available for the treatment of melanoma. The combination of these drugs is considered investigational in the treatment of advanced colorectal cancer.The study doctor can explain how the study drugs are designed to work.

Up to 84 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalCohort 1 comprised of patients with detectable EGFR S492R or other ectodomain mutations in circulating free tumor DNA. Participants receive Panitumumab until disease progression. If the disease appears to get worse, participants may be able to cross-over to group 2 and begin to receive the panitumumab and trametinib combination therapy.
  • Panitumumab
    Cohort 2ExperimentalCohort 2 comprised of patients with detectable KRAS or NRAS mutations in exons 2, 3, or 4; or BRAF codon 600 mutations in circulating free tumor DNA. Participants receive Panitumumab and Trametinib combination therapy until disease progression.
    • Panitumumab
    • Trametinib
    Cohort 3ExperimentalCohort 3 comprised of patients who do not have any of the detectable mutations listed in Cohort 1 or 2. Participants receive Panitumumab until disease progression. If the disease appears to get worse, participants may be able to cross-over to group 2 and begin to receive the Panitumumab and Trametinib combination therapy.
    • Panitumumab

      Eligibility Criteria

      Inclusion Criteria:

      1. Histologically or cytologically confirmed colorectal adenocarcinoma, with metastatic disease documented on diagnostic imaging studies

      2. Progression during or within 6 months after fluoropyrimidine, irinotecan, and oxaliplatin. For oxaliplatin-based therapy, failure of therapy will also include patients who progressed within 12 months of adjuvant therapy and patients who had oxaliplatin discontinued secondary to toxicity or allergic reaction. Patients with a known history of Gilbert's disease who cannot receive irinotecan or patients who are intolerant of irinotecan or fluoropyrimidine are eligible.

      3. Confirmed wild-type status in KRAS exons 2, 3, and 4; NRAS exons 2, 3, and 4; and BRAF, by standard of care testing of tumor specimen. Tissue used for testing may have been collected prior to treatment with cetuximab.

      4. Patient must have been already tested and have available results of the mutations status of KRAS/NRAS/BRAF and EGFR from the circulating tumor DNA within 10 weeks prior to starting study therapy.

      5. Previous treatment with cetuximab with evidence of clinical benefit, as defined by complete response, partial response, or prolonged stable disease with 16 or more weeks of treatment without radiographic progression, as assessed by the treating physician and documented in the medical record. This treatment may have occurred at any point in the patient's clinical course for treatment of metastatic colorectal cancer.

      6. Ultimate progression through previous treatment with cetuximab, with documented clinical progression. Patients who discontinued cetuximab for any other reason, such as decline in performance status, hypersensitivity, or other adverse effects of therapy, are not eligible.

      7. All prior treatment- related toxicities must be CTCAE (Version 4.0) </= Grade 1 (except </= Grade 2 for alopecia or peripheral neuropathy).

      8. Radiographically measurable disease present per RECIST 1.1

      9. Age >/= 18 years

      10. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

      11. Blood counts performed within 3 weeks prior to starting study therapy must have absolute neutrophil count >/= 1,500/mm3, platelets >/= 100,000/mm3, and hemoglobin >/= 9 g/dL

      12. Liver function tests performed within 3 weeks prior to starting study therapy must have total bilirubin </= 1.5 x upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase </= 2.5 x ULN (or </= 5 x ULN if liver metastases are present), and albumin >/= 2.5 g/dL

      13. Serum creatinine performed within 3 weeks prior to starting study therapy must be </= 1.5 x ULN, or have calculated creatinine clearance (using Cockcroft-Gault formula) of >/= 50 mL/minute.

      14. PT/INR and PTT performed within 3 weeks prior to starting study therapy must be </= 1.5 x ULN

      15. Left Ventricular Ejection fraction (LVEF) >/= LLN by ECHO or MUGA within 3 weeks prior to starting study therapy.

      16. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and must agree to use effective contraception throughout the treatment period and for 4 months after the last dose of study treatment.

      17. Ability to sign informed consent form. Informed consent form for this study must be signed prior to the performance of any study-specific procedures and initiation of any study therapy.

      18. Ability to swallow and retain oral medication, with no clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

      19. In cohort 1, must have EGFR S492R or other ectodomain mutation detected from circulating tumor DNA from plasma collected after progression to prior cetuximab. May have a concomitant mutation in KRAS, NRAS, or BRAF, if there is at least a 5-fold higher allele frequency of the most prevalent EGFR mutation than the most prevalent KRAS/NRAS/BRAF mutation.

      20. In cohort 2, must have one or more mutations found in KRAS exon 2, 3, or 4; NRAS exon 2, 3, or 4; BRAF codon 600. May have a concomitant EGFR ectodomain mutation, if the most prevalent EGFR ectodomain mutation does not have over a 5-fold higher allele frequency than the most prevalent KRAS/NRAS/BRAF mutation.

      21. In cohort 3, must not have EGFR ectodomain mutation or any mutations in KRAS, NRAS, or BRAF.

      22. Patients must have consented to the MD Anderson ATTACC protocol prior to inclusion.

      Exclusion Criteria:

      1. Past treatment with any MEK or ERK inhibitor or with panitumumab

      2. Previous retreatment with cetuximab following progression on initial course of cetuximab therapy

      3. Known untreated brain metastasis or brain metastasis treated within 3 months prior to enrollment in this trial

      4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.

      5. History of interstitial lung disease or pneumonitis

      6. History of any other malignancy within 3 years, except for adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer and/or subjects with indolent second malignancies are eligible.

      7. Prior treatment within 21 days of the first dose of study drug with any other chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment, or failure to recover from adverse effects of prior therapies administered over 4 weeks prior to Study Day 1. All toxicities from prior therapies must be </= Grade 1 (or </= Grade 2 for alopecia or peripheral neuropathy). Prior systemic treatment in the adjuvant setting is allowed.

      8. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to randomization and/or daily chemotherapy without the potential for delayed toxicity within 14 days prior to randomization.

      9. Impaired cardiac function or clinically significant cardiac disease, as defined: a) Left ventricular ejection fraction < lower limit of normal (LLN) on multiple gated acquisition scan (MUGA) or echocardiogram; b) Congenital long QT syndrome or family history of unexpected sudden cardiac death; c) QTc corrected with Bazett's formula (QTcB) >/= 480 ms.; d) History or evidence of current clinically significant uncontrolled arrhythmias. Note subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible;

      10. Continuation of criteria above: e) History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; f) History or evidence of current >/= Class II congestive heart failure as defined by New York Heart Association (NYHA); g) Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy; h) Patients with intra-cardiac defibrillators.

      11. Any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent, or compliance to the study procedures.

      12. History of retinal vein occlusion (RVO)

      13. Pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment.

      14. History of organ allograft or other history of immunodeficiency.

      15. Inability or unwillingness to comply with study and/or follow-up requirements

      16. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

      17. Known Human Immunodeficiency Virus (HIV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.

      18. Current use of a prohibited medication.

      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Response Rate (RR)
      Time Frame:Day 10 of Cycle 4 (14 day cycles) and every 4 cycles until 28-35 days after last dose of study drug
      Safety Issue:
      Description:Response rate (RR) defined Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.

      Secondary Outcome Measures

      Details

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

      Trial Keywords

      • Colorectal cancer
      • Colorectal adenocarcinoma
      • EGFR S492R or other ectodomain mutations in circulating free tumor DNA
      • Detectable KRAS or NRAS mutations in exons 2, 3, or 4; or BRAF codon 600 mutations in circulating free tumor DNA
      • No detectable mutations in circulating free tumor DNA
      • Panitumumab
      • Vectibix
      • Trametinib
      • GSK1120212

      Last Updated

      April 10, 2017