Merestinib in Treating Patients with Breast Cancer Metastatic in the Bone
This phase IB trial studies the side effects and best dose of merestinib in treating patients with breast cancer that has spread to the bones. Merestinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Inclusion Criteria
- INCLUSION CRITERIA FOR URINARY SCREENING
- Post-menopausal or undergoing ovarian suppression
- Histological diagnosis of female breast cancer
- INCLUSION CRITERIA FOR TREATMENT
- At least one bone metastases must be present
- Urinary N-telopeptide level above 20nM bone collagen equivalent (BCE)/mM creatinine measured at ARUP
- Archived or freshly biopsied primary and/or bone metastatic tumor tissue available in paraffin-embedded blocks or slides that is expected to yield 9 slides
- Life expectancy of >= 6 months
- Toxicity related to prior treatments must either have resolved to grade 1 or less, returned to baseline, or be deemed irreversible
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (within 28 days prior to enrollment)
- Planning to remain on current breast cancer therapy for at least 12 weeks
- At least one prior line of therapy for metastatic breast cancer
- Concurrent treatment with bisphosphonates or denosumab is required
Exclusion Criteria
- Unable to swallow or take anything orally
- Electrocardiogram (ECG) abnormalities: * Prolonged QTcF (Fridericia’s correction) interval on screening ECG (>= 450 msec) * QRS ˃ 120 msec * PR ˃ 210 msec * Any prior history, or current evidence of second- or third-degree heart block * Heart rate ˂ 40 beats per minute at screening * ECG second degree heart block (Mobitz’s type 2 or Wenckebach) * Complete heart block * Left bundle branch block or bifascicular block (right bundle branch block and left anterior hemiblock together) * Episodes of ventricular tachycardia
- Any known prior malignancy (not including non-melanoma skin cancers), unless treated with curative intent
- A serious uncontrolled medical disorder or active infection, which would impair the ability of the subject to receive protocol therapy
- Current or recent (within 3 months) gastrointestinal disease that could impact the absorption (i.e., unmanageable diarrhea or malabsorption at the time of screening)
- Absolute neutrophil count (ANC) ˂ 1,500 cells/mm^3
- Platelet count ˂ 100,000 cells/mm^3
- Hemoglobin ˂ 9 g/dL
- Total bilirubin ˃ 1.5 x institutional upper limit of normal (IULN) (unless due to diagnosis of Gilbert’s syndrome)
- Alanine aminotransferase (alanine aminotransaminase [ALT]) and aspartate aminotransferase (aspartate aminotransaminase [AST]) ˃ 2.5 x IULN
- Serum creatinine ˃ 1.5 x ULN
- Prothrombin time (PT)/partial thromboplastin time (PTT) ˃ 1.5 times the ULN
- Serum sodium, potassium, and calcium levels not within normal limits
- Any atrophic macular condition including intermediate or advanced age-related macular degeneration
- Patients receiving medications that are known to be substrates of CYP2C8 (including paclitaxel), CYP2C9, or CYP2C19 or to be oral substrates of CYP3A with narrow therapeutic window; subjects who have discontinued any of these medications must have a wash-out period of at least 5 days or 5 half-lives of the drug (whichever is longer) prior to the first dose of merestinib
- Exposure to any investigational drug or placebo within 4 weeks of enrollment
- Any other sound medical, psychiatric, and/or social reasons as determined by the investigator
- History of diseases with influence on bone metabolism, such as Paget’s disease, osteogenesis imperfecta, active primary or secondary hyperparathyroidism, and primary or secondary hyperthyroidism within 12 months prior to study entry
- Patients with known symptomatic brain metastasis; subjects with controlled brain metastasis (no radiographic progression at least 4 weeks following radiation and/or surgical treatment and no neurological signs or symptoms) will be allowed
- History of allergy to merestinib or chemically related compounds
- History of osteonecrosis of the jaw
- Change in chemotherapy or hormone therapy =< 8 weeks prior to of the start of the study
- Active gout or inflammatory arthritis requiring treatment
- Use within 28 days of registration of calcitonin, recombinant parathyroid hormone-related peptides, mithramycin, radium, strontium ranelate, or gallium nitrate
- Adult patients who require monitored anesthesia for PET scanning due to claustrophobia
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03292536.
PRIMARY OBJECTIVES:
I. To assess the tolerability of merestinib in combination with standard breast cancer therapies.
II. To measure the change in urinary N-telopeptide level after 12 weeks of therapy with merestinib.
SECONDARY OBJECTIVES:
I. To measure the absolute and percentage change in serum beta–CTX, TRAP-5b, P1NP, and bone specific alkaline phosphatase (BSAP) at time points from baseline to 12 weeks.
II. To evaluate determine time to skeletal-related event(s) following initiation of merestinib dosing.
III. To evaluate change in pain (as measured by pain scores and narcotic use) during and after 12 weeks of merestinib treatment.
IV. To evaluate the change in bone lesion uptake on sodium fluoride (NaF) positron emission tomography (PET) scan after 12 weeks of merestinib treatment.
EXPLORATORY OBJECTIVES:
I. To measure macrophage stimulating protein (MSP) levels in serum/plasma and tumor (when available) and determine whether MSP levels correlate with response to merestinib.
II. To measure RON and phosphorated (p)RON levels in pretreatment tumor biopsy samples (when available) and determine whether RON or pRON levels correlate with response to merestinib.
III. To collect peripheral blood leukocytes at time points for future immunophenotyping, to assess markers of immune response.
IV. To collect tumor biopsy samples (when available) for future assessment of tumor-infiltrating lymphocytes (TILs) and determine whether TILs correlate with response to merestinib and to compare TIL clones using single cell sequencing.
OUTLINE: This is a dose escalation study.
Patients receive merestinib orally (PO) once daily (QD). Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationHuntsman Cancer Institute/University of Utah
Principal InvestigatorAdam Louis Cohen
- Primary IDHCI103657
- Secondary IDsNCI-2017-01924, 103657
- ClinicalTrials.gov IDNCT03292536