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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, HER3/4 Mutation or KRAS Mutation

NCT03065387

Description:

Objectives: Primary Objectives: To evaluate the safety and tolerability of neratinib when combined with one of the following agents: Arm 1: Everolimus (mTOR inhibitor) Arm 2: Palbociclib (CDK 4/6 inhibitor) Arm 3: Trametinib (MEK inhibitor) To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of neratinib combination therapy. Secondary Objectives: To determine preliminary anti-tumor efficacy of neratinib combination therapy. To determine pharmacodynamic markers in tissue, blood and plasma that may predict outcome. To explore the potential of drug-drug interactions by evaluating the pharmacokinetic profile of each agent when administered in these combinations: neratinib+everolimus, neratinib+palbociclib, and neratinib+trametinib and blood-based biomarkers.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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, HER3/4 Mutation or KRAS Mutation
  • Official Title: Phase I 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, HER3/4 Mutation or KRAS Mutation

Clinical Trial IDs

  • ORG STUDY ID: 2016-0430
  • SECONDARY ID: NCI-2018-01218
  • NCT ID: NCT03065387

Conditions

  • Malignant Neoplasm of Breast
  • Malignant Neoplasms of Digestive Organs
  • Malignant Neoplasms of Female Genital Organs
  • Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites
  • Malignant Neoplasms of Independent (Primary) Multiple Sites
  • Malignant Neoplasms of Lip Oral Cavity and Pharynx
  • Malignant Neoplasms of Mesothelial and Soft Tissue
  • Malignant Neoplasms of Respiratory and Intrathoracic Organs
  • Malignant Neoplasms of Thyroid and Other Endocrine Glands
  • Malignant Neoplasms of Urinary Tract
  • Neoplasms of Uncertain or Unknown Behavior

Interventions

DrugSynonymsArms
NeratinibNeratinib and Everolimus
EverolimusAfinitor, Zortress, RAD001Neratinib and Everolimus
PalbociclibPD-0332991, IbranceNeratinib and Palbociclib
TrametinibNeratinib and Trametinib

Purpose

Objectives: Primary Objectives: To evaluate the safety and tolerability of neratinib when combined with one of the following agents: Arm 1: Everolimus (mTOR inhibitor) Arm 2: Palbociclib (CDK 4/6 inhibitor) Arm 3: Trametinib (MEK inhibitor) To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of neratinib combination therapy. Secondary Objectives: To determine preliminary anti-tumor efficacy of neratinib combination therapy. To determine pharmacodynamic markers in tissue, blood and plasma that may predict outcome. To explore the potential of drug-drug interactions by evaluating the pharmacokinetic profile of each agent when administered in these combinations: neratinib+everolimus, neratinib+palbociclib, and neratinib+trametinib and blood-based biomarkers.

Trial Arms

NameTypeDescriptionInterventions
Neratinib and EverolimusExperimentalNeratinib by mouth 1 time a day with food, preferably in the morning, every day. Everolimus by mouth 1 time a day with Neratinib every day. Study cycle is 28 days.
  • Neratinib
  • Everolimus
Neratinib and PalbociclibExperimentalPalbociclib by mouth 1 time a day with Neratinib, every day for 3 weeks followed by a 1-week "rest period" during each cycle. Study cycle is 28 days.
  • Neratinib
  • Palbociclib
Neratinib and TrametinibExperimentalTrametinib by mouth 1 time a day with Neratinib every day. Study cycle is 28 days.
  • Neratinib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects with advanced or metastatic solid tumors that are refractory to standard
             therapies known to provide clinical benefit. 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
             (patients with 3+ results on immunohistochemistry testing for EGFR may be allowed to
             enroll if gene amplification results are unavailable); c. HER2 gene amplification
             (patients with 3+ results on immunohistochemistry testing for Her-2 may be allowed to
             enroll if gene amplification results are unavailable); d. Somatic mutation in KRAS
             (Patients will be enrolled only on neratinib and trametinib combination ARM).

          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 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 2 - Neratinib and Palbociclib : Any prior neuropathy
             should be back to baseline or grade 1

         13. 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.

         14. 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.

         15. 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.

        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 Fredericia method of QTc analysis

          9. Has known primary brain tumor, active central nervous system (CNS) metastases and/or
             carcinomatous meningitis. Subjects with previously treated brain metastases may
             participate provided they are clinically stable with no neurological symptoms, 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of Neratinib Combination Therapy
Time Frame:28 days
Safety Issue:
Description:MTD defined as the highest dose at which no more than 1 of 6 evaluable subjects has had a dose limiting toxicity (DLT). DLT defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and occurring during the first cycle on study.

Secondary Outcome Measures

Measure:Anti-Tumor Efficacy of Neratinib Combination Therapy evaluated by objective response by RECIST v1.1
Time Frame:Every 8 weeks for 6 months
Safety Issue:
Description:Anti-tumor efficacy of Neratinib combination therapy evaluated by objective response by RECIST v1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Metastatic solid tumors
  • Genetic mutation
  • Biomarkers
  • Neratinib
  • Everolimus
  • Afinitor
  • Zortress
  • RAD001
  • Palbociclib
  • PD-0332991
  • Ibrance
  • Trametinib

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