Patient case: 54-year-old male with melanoma; genetic feature: BRAF (V600K)

Clinical trial: Study of the Pan-ERBB Inhibitor Neratinib Given in Combination With Everolimus, Palbociclib or Trametinib in Advanced Cancer Subjects With EGFR Mutation/Amplification, HER2 Mutation/Amplification or HER3/4 Mutation

Summary: There are 2 parts to this clinical research study: Part 1 (dose escalation) and Part 2 (expansion).
  The goal of Part 1 of this study is to find the highest tolerable dose of neratinib in combination with everolimus, Ibrance (palbociclib), or trametinib that can be given to patients who have advanced cancer with a specific mutation (EGFR, HER2, HER3, or HER4).
  The goal of Part 2 of this study is to learn if the dose of neratinib in combination with everolimus, Ibrance (palbociclib), or trametinib found in Part 1 can help to control advanced cancer in patients who have a specific mutation.
  The safety of this drug will also be studied in both parts of the study.

Detailed description: Study Groups:
  Depending on the type of disease and when participant joins the study, participant will receive 1 of 3 drug combinations:
  -  Group A: Neratinib and Everolimus
  -  Group B: Neratinib and Palbociclib
  -  Group C: Neratinib and Trametinib
  Up to 40 participants will be enrolled in each study group.
  If participant is found to be eligible to take part in this study, participant will be assigned a study drug dose based on when participant joins this study. About 3-6 participants will be enrolled per study drug dose.
  If participant is in Part 2, participant will receive neratinib in combination with everolimus, palbociclib, or trametinib at the highest dose that was safe and tolerated in Part 1.
  A total of about 18-90 participants will be enrolled in Part 1 of the study. About 10 participants will be enrolled per group and up to a total of 30 participants will be enrolled in Part 2.
  If participant is in Part 1, the dose of neratinib in combination with everolimus, palbociclib, or trametinib you receive will depend on when participant joins this study.
  The study doctor will let you know what study group and which part of the study you participant is participating in.
  Study Drug Administration:
  Each study cycle is 28 days. The following directions are for participants in both Part 1 and Part 2.
  Participant will take neratinib by mouth 1 time a day with food, preferably in the morning, every day. If participant misses any dose(s) of neratinib, do not make up the missed dose(s). However, if it has been less than 6 hours since participant was meant to take participant's dose, participant may take participant's dose that day as soon as participant remembers. It is important that participant takes neratinib at the same time every day. Neratinib must be stored at room temperature and out of direct sunlight.
  There will be a 30 minute waiting period between participant's dose of neratinib and participant's other study drug(s) during Cycle 1. After that, there is no waiting period.
  If participant is in Group A, participant will take everolimus by mouth 1 time a day with neratinib every day. Everolimus must be stored at room temperature, kept dry and away from light.
  If participant is in Group B, participant will take palbociclib by mouth 1 time a day with neratinib, every day for 3 weeks followed by a 1-week "rest period" during each cycle. Palbociclib must be stored at room temperature.
  If participant is in Group C, participant will take trametinib by mouth 1 time a day with neratinib every day. Trametinib must be stored in a refrigerator (do not freeze), kept dry and away from light.
  Participant will also take Imodium™ (loperamide) to lower the risk of diarrhea caused by neratinib. Along with participant's first dose of neratinib, participant will take 2 tablets of loperamide by mouth 3 times a day for the first 14 days of Cycle 1. After that, participant will take 2 tablets 2 times a day for the rest of Cycle 1. After Cycle 1, participant will take loperamide as needed. If diarrhea continues despite taking loperamide, participant should call participant's doctor or nurse. If participant is constipated, participant should call participant's study doctor but should not discontinue Imodium use unless specifically instructed by participant's doctor.
  Participant's study doctor or staff will contact participant on each of the first 3 days after participant starts taking neratinib to ask if participant has diarrhea and to make any changes to participant's treatment. Participant's study doctor will give participant a separate instruction sheet that will explain how to manage diarrhea.
  Participant will receive a study drug diary in which participant will record the date and time of each dose of study drugs. Participant's study doctor will also tell participant to record the number of stools participant has per day and the dose of loperamide participant takes each day for the first cycle of therapy. Participant will need to record all doses of study drugs for the entire study. Participant will need to bring the diary to participant's study visits. Participant must also bring any unused study drug and the pill bottles (even if empty) to the clinic on Day 1 of each cycle.
  Length of Treatment:
  Participant may continue taking the study drugs for as long as the doctor thinks it is in participant's best interest. Participant will no longer be able to take the study drug 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 Cycle 1 (some of these tests will not be performed if participant had them the last 72 hours):
  -  Participant will have a physical exam.
  -  Blood (about 4-5 teaspoons) and urine will be collected for routine tests.
  -  Blood (about 4 teaspoons) will be drawn for biomarker testing, including genetic biomarkers.
  -  Participant will have an EKG to check participant's heart function.
  -  If participant can become pregnant, blood (about 1 teaspoon) will be drawn for a pregnancy test.
  On Days 2-4 of Cycle 1, the study staff will call participant to ask about any symptoms participant may be having. The call should last about 5 minutes.
  On Days 8, 15, and 22 of Cycle 1:
  -  Participant will have a physical exam.
  -  Blood (about 4-5 teaspoons) will be drawn for routine tests.
  -  Blood (about 4 teaspoons) will be drawn for biomarker testing, including genetic biomarkers.
  -  On Day 15 only, blood (about 1 teaspoon each time) will be drawn before and then 5 times over the next 5 hours after study drugs dose for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the blood at different time points.
  -  If participant is in Part 2, on Day 15 only, participant will have a core or excisional biopsy for biomarker testing (including genetic biomarkers).
  On Day 16 of Cycle 1 (about 20-28 hours after participant's Day 15 dose of study drugs), blood (about 1 teaspoon) will be drawn for PK testing.
  On Day 1 of Cycles 2 and beyond:
  -  Participant will have a physical exam.
  -  Blood (about 4-5 teaspoons) and urine will be drawn for routine tests.
  -  Blood (about 4 teaspoons) will be drawn for biomarker testing, including genetic biomarkers.
  On Day 1 of Cycles 3 and 5, blood (about 1 teaspoon) will be drawn before the study drug dose for PK testing.
  Every 8 weeks, participant will have a CT scan or MRI to check the status of the disease. After 6 months, participant will have a CT scan or MRI scan every 12 weeks.
  Every 12 weeks, participant will have an ECHO or MUGA scan.
  Participant may have eye exams (Group C only) and other routine tests performed if the study doctor thinks they are needed.
  End-of-Treatment Visit:
  After participant's last study drug dose:
  -  Participant will have a physical exam.
  -  Blood (about 6 teaspoons) and urine will be collected for routine tests and to check how well participant's blood clots.
  -  Blood (about 4 teaspoons) will be drawn for biomarker testing.
  -  Participant may have an ECHO or MUGA scan. This scan will not be performed if participant had them done in the last 12 weeks.
  -  Participant will have a CT scan or MRI to check the status of the disease.
  If participant goes off study because the disease gets worse, participant will be called every 3 months for 1 year. Participant will be asked about how participant is doing and if participant has received any new treatment for cancer. The calls should last about 15 minutes.
  Follow-up Visits:
  About 30 days after participant's last dose of study drug, blood (about 4-5 teaspoons) and urine will be collected for routine tests.
  This is an investigational study. Neratinib is not FDA approved or commercially available. It is currently being used for research purposes only. Everolimus is commercially available and FDA approved for the treatment of several disease types, including breast cancer and renal cell carcinoma. Palbociclib is commercially available and FDA approved for the treatment of ER-positive, HER2-negative breast cancer. Trametinib is commercially available and FDA approved for the treatment of melanoma with BRAF V600E or V600K mutations.
  The study doctor can explain how the study drug is designed to work.
  Up to 120 participants will be enrolled in this study. All will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Subjects with advanced or metastatic solid tumors that are refractory to standard therapy or have relapsed after standard therapy. Subjects with hematologic malignancy including lymphoma/myeloma will not be enrolled on this study.
  2. Subjects must have one of the following: a. somatic mutations in human epidermal growth factor receptor (EGFR, HER2, HER3, and HER4); b. EGFR gene amplification; c. HER2 gene amplification
  3. Subjects must have measurable disease by RECIST v1.1.
  4. Subjects must be >/=18 years of age.
  5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  6. Abnormal organ function is permitted. However, subjects must have: a. absolute neutrophil count >/= 1500/mL; b. platelets >/= 100,000/mL; c. hemoglobin >/= 9 g/dL; d. creatinine </= 1.5 X upper limit of normal (ULN); e. total bilirubin </= 1.5 X ULN; f. aspartate aminotransferase (AST/SGOT) and/or alanine aminotransferase (ALT/SGPT) </= 2.5 X ULN (</=5 X ULN in subjects with bone or liver metastases)
  7. Subjects must be >/=4 weeks beyond treatment with any chemotherapy or other investigational therapy to include hormonal, biological, or targeted agents; or at least 5 half-lives from hormonal, biological, or targeted agents, whichever is shorter at the time of treatment initiation.
  8. Women of child-bearing potential MUST have a negative serum or urine human chorionic gonadotropin (HCG) test unless prior hysterectomy or menopause (defined as 12 consecutive months of amenorrhea). Subjects should not become pregnant or breastfeed while on this study. Sexually active subjects must agree to use contraception for the duration of study participation and for 4 months after the last dose of neratinib and everolimus, palbociclib or trametinib.
  9. Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures.
  10. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: Fasting lipid profile: Cholesterol less than or equal to 350 mg/dL and triglycerides less than or equal to 400 mg/dL.
  11. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: Patients who are taking medications with moderate or potent inhibitors or inducers of CYP450 3A4 should be off for 5 half-lives prior to starting everolimus.
  12. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: Monitor serum glucose levels in subjects with preexisting diabetes or hyperglycemia
  13. Only for subjects enrolled in Arm 2 - Neratinib and Palbociclib: Any prior neuropathy should be back to baseline or grade 1
  14. Only for subjects enrolled in Arm 2 - Neratinib and Palbociclib: Patients who are taking medications with moderate or potent inhibitors or inducers of CYP450 3A4 should be off for 5 half-lives prior to starting Palbociclib.
  15. Only for subjects enrolled in Arm 3 - Neratinib and Trametinib: All skin rash (dermatitis acneiform, erythema, xeroderma, eczema) should be at grade 1 when starting trametinib treatment.
  16. Only for subjects enrolled in Arm 3 - Neratinib and Trametinib: History of retinal disorder, dry eye syndrome, or blurry vision need to be evaluated by ophthalmology prior to starting treatment.
  17. Only for subjects enrolled in Arm 3 - Neratinib and Trametinib: Monitor serum glucose levels in subjects with preexisting diabetes or hyperglycemia
  Exclusion Criteria:
  1. Subjects who are pregnant or breastfeeding;
  2. Known Hepatitis B, Hepatitis C or human immunodeficiency virus (HIV) infection.
  3. Inability or unwillingness to swallow pills.
  4. Active infection requiring intravenous (IV) antibiotics or other uncontrolled intercurrent illness requiring hospitalization.
  5. Clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels. For example, subjects should have no more than 50% of the large intestine removed and no sign of malabsorption (e.g. gastrectomy, ileal bypass, chronic diarrhea, Crohn's disease, malabsorption, gastroparesis).
  6. Inability to comply with the study and follow-up procedures.
  7. History of cerebrovascular accident (CVA), myocardial infarction or unstable angina within the previous 6 months before starting therapy.
  8. Prolongation of QT/QTc interval (QTc interval >450 ms for males or >470 ms for females) using the Fridericia method of QTc analysis.
  9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless or clinical stability.
  10. Uncontrolled concurrent disease or illness including but not limited to: - symptomatic congestive heart failure (NYHA Class III or IV) per the NYHA Classification (see Appendix B), unstable angina pectoris, clinically significant cardiac arrhythmia; - unstable or untreated cardiac conditions or ejection fraction of <50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA); - diabetes mellitus (i.e. fasting blood glucose >220 despite acceptable chronic diabetes therapy); - psychiatric illness that would limit compliance with study requirements, as determined by the investigator
  11. Participating in any other clinical trials using an investigational product.
  12. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: History of hypersensitivity to everolimus
  13. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: Subjects requiring therapy with immunosuppressive agents such as anti-tumor necrosis factor alpha (TNFa) agents (Etanercept, Adalimumab), azathioprine, methotrexate, cyclosporine, etc for active autoimmune disorder.
  14. Only for subjects enrolled in Arm 1 - Neratinib and Everolimus: Major surgery </=28 days prior to treatment with everolimus.
  15. Only for subjects enrolled in Arm 3 - Neratinib and Trametinib: Albumin less than 3 Gm/dL

Relevance to patient case: not relevant