ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03065387
Recruitment Status : Recruiting
First Posted : February 27, 2017
Last Update Posted : March 29, 2018
Sponsor:
Collaborator:
Puma Biotechnology, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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.

This is an investigational study. Neratinib is FDA approved and commercially available for the treatment of certain early-stage HER2-positive breast cancer. 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 use of this combination to treat advanced cancer with a specific mutation is investigational.

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.


Condition or disease Intervention/treatment Phase
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 Drug: Neratinib Drug: Everolimus Drug: Palbociclib Drug: Trametinib Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 or HER3/4 Mutation
Actual Study Start Date : October 31, 2017
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : October 2023


Arm Intervention/treatment
Experimental: Neratinib and Everolimus

Neratinib 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.

Drug: Neratinib

Starting Dose of Neratinib - Dose Escalation Phase: 160 mg by mouth daily in a 28 day cycle.

Starting Dose of Neratinib - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.


Drug: Everolimus

Starting dose of Everolimus - Dose Escalation Phase: 5 mg by mouth every other day of a 28 day cycle.

Starting Dose of Everolimus - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.

Other Names:
  • Afinitor
  • Zortress
  • RAD001

Experimental: Neratinib and Palbociclib

Palbociclib 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.

Drug: Neratinib

Starting Dose of Neratinib - Dose Escalation Phase: 160 mg by mouth daily in a 28 day cycle.

Starting Dose of Neratinib - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.


Drug: Palbociclib

Starting dose of Palbociclib - Dose Escalation Phase: 75 mg by mouth every other day for 3 weeks followed by a 1-week "rest period" during each cycle.

Starting dose of Palbociclib - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.

Other Names:
  • PD-0332991
  • Ibrance

Experimental: Neratinib and Trametinib

Trametinib by mouth 1 time a day with Neratinib every day.

Study cycle is 28 days.

Drug: Neratinib

Starting Dose of Neratinib - Dose Escalation Phase: 160 mg by mouth daily in a 28 day cycle.

Starting Dose of Neratinib - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.


Drug: Trametinib

Starting dose of Trametinib - Dose Escalation Phase: 1 mg by mouth daily for 5 days on and 2 days off in Cycle -1. Dose level -2 is 4 days on and 3 days off.

Starting dose of Trametinib - Dose Expansion Phase: Maximum tolerated dose from Dose Escalation Phase.





Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Neratinib Combination Therapy [ Time Frame: 28 days ]
    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 :
  1. Anti-Tumor Efficacy of Neratinib Combination Therapy evaluated by objective response by RECIST v1.1 [ Time Frame: Every 8 weeks for 6 months ]
    Anti-tumor efficacy of Neratinib combination therapy evaluated by objective response by RECIST v1.1.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
  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 Fridericia 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03065387


Contacts
Contact: Sarina Piha-Paul, MD 713-563-1930 spihapau@mdanderson.org

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Puma Biotechnology, Inc.
Investigators
Principal Investigator: Sarina Piha-Paul, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03065387     History of Changes
Other Study ID Numbers: 2016-0430
First Posted: February 27, 2017    Key Record Dates
Last Update Posted: March 29, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Metastatic solid tumors
Everolimus
Afinitor
Zortress
RAD001
Genetic mutation
Biomarkers
Neratinib
Palbociclib
PD-0332991
Ibrance
Trametinib

Additional relevant MeSH terms:
Neoplasms
Breast Neoplasms
Genital Neoplasms, Female
Urologic Neoplasms
Lip Neoplasms
Thyroid Neoplasms
Neoplasms by Site
Urogenital Neoplasms
Mouth Neoplasms
Head and Neck Neoplasms
Endocrine Gland Neoplasms
Everolimus
Sirolimus
Breast Diseases
Skin Diseases
Lip Diseases
Mouth Diseases
Stomatognathic Diseases
Endocrine System Diseases
Thyroid Diseases
Palbociclib
Trametinib
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents