64-Cu Labeled Brain PET/MRI for MM-302 in Advanced HER2+ Cancers With Brain Mets

Study Overview
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Brief Summary
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This is a single arm pilot study of 64Cu-MM-302 and unlabeled MM-302 in combination with trastuzumab in 10 patients with advanced HER2+ cancer with new or progressive brain metastases. Patients will receive standard imaging at baseline, including FDG-PET/CT plus MR brain imaging. Patients will subsequently start protocol therapy with MM-302 and trastuzumab given on day 1 of an every 21-day dosing cycle, at the recommended phase 2 dose of 30 mg/m2. Patients will receive 64Cu-labeled MM-302 (3-5 mg/m2 doxorubicin) three hours after unlabeled dose of MM-302. Integrated MR/PET imaging of the brain and whole body will be performed at two time points following 64Cu-labeled MM-302 administration: (1) within 3 hours (+/- 1 hour) of labeled drug injection, and (2) 24 hours (+/- 6 hours) post-injection. Patients will continue to receive subsequent doses of unlabeled MM-302 plus trastuzumab every 3 weeks until clinical or radiographic disease progression (either in the brain or systemically) or unacceptable toxicity, whichever occurs soonest. MR brain imaging and FDG-PET/CT scans will be performed every 9 weeks to monitor for treatment response and disease progression.

Official Title
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A Pilot Study of 64-Cu Labeled Brain PET/MRI for MM-302, a Novel HER2 Targeting Agent, in Advanced HER2+ Cancer With Brain Metastases

Conditions
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Brain Metastases, Documented Her2 Overexpression, Advanced Solid Tumor, Neurologically Stable

Intervention / Treatment
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* Drug: MM-302
* Drug: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed advanced solid tumor malignancy with documented HER2 overexpression or gene amplification on prior archival tumor tissue by CLIA-certified laboratory New or progressive brain metastases with at least one metastasis measuring ≥ 1 cm in longest diameter on MR imaging Patients may have extra-cranial metastatic disease but this is not required for study entry Neurologically stable as defined by ALL of the following: Stable or decreasing dose of steroids and anti-convulsants for at least 14 days prior to study entry No clinically significant mass effect, midline shift, or impending herniation on baseline brain imaging No significant focal neurologic signs and/or symptoms which would necessitate radiation therapy or surgical decompression in the judgment of the treating clinician Prior radiation therapy for treatment of brain metastases completed at least 4 weeks prior to study entry Prior radiation therapy for brain metastases allowed but must have been at least 4 weeks prior to study entry and follow up imaging is not consistent with pseudoprogression in the judgment of treating clinician Patients must be ambulatory with ECOG performance status of 0 - 1. Adequate organ function, including absolute neutrophil count (ANC) ≥1500 cells/uL, hemoglobin ≥9.0 gm/dL, platelets ≥100,000 cells/uL, estimated creatinine clearance ≥50 mL/min (by the Cockcroft Gault equation), bilirubin <1.5x ULN (unless Gilbert's is suspected), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <1.5x ULN (< 3x ULN if known liver metastases). Ejection fraction as assessed by MUGA or echocardiogram > 50% Prior cumulative doxorubicin exposure < 300 mg/m2 (or epirubicin equivalent) Last dose of prior systemic anti-cancer therapy administered at least 5 half-lives or 4 weeks prior to study entry, whichever is shorter No contra-indications to MRI (e.g. pacemaker, aneurysm clips, severe claustrophobia) Patients will sign a study-specific IRB-approved consent prior to study entry. Patients must be able and willing to consent and undergo study procedures. Age ≥18 years old Exclusion Criteria: Prior treatment with MM-302 Patients with any class of New York Heart Association (NYHA) CHF or heart failure with preserved ejection fraction (HFPEF) Patients with a history of known coronary artery disease or a myocardial infarction within the last 12 months Patients with persistently uncontrolled hypertension (systolic BP > 160 mm Hg or diastolic BP > 100 mm Hg) despite optimal medical therapy Patients with known unstable angina pectoris Patients with a known history of serious cardiac arrhythmias requiring treatment (exception: controlled atrial fibrillation, paroxysmal supraventricular tachycardia) Patients with a prolonged QTc interval (≥ 450 ms) Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity Patients with a history of LVEF decline to below 50% during or after prior trastuzumab/lapatinib or other HER2 directed therapy. Current dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy. Any serious and/or unstable pre-existing medical, psychiatric, or other medical condition that could interfere with subject's safety, provision of informed consent, or compliance with study procedures Presence of leptomeningeal disease in the absence of parenchymal brain metastases

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm Study - Arm 1<br>10 patients will receive standard imaging at baseline, incl. FDG-PET/CT plus MR brain imaging. Patients will subsequently start protocol therapy with MM-302 and trastuzumab given on day 1 of an every 21-day dosing cycle, at recommended phase 2 dose of 30 mg/m2. Patients will receive 64Cu-labeled MM-302 (3-5 mg/m2 doxorubicin) 3 hours after unlabeled dose of MM-302. Integrated MR/PET imaging of brain and whole body will be performed at 2 time points following 64Cu-labeled MM-302 administration: (1) within 3 hours (+/- 1 hour) of labeled drug injection, and (2) 24 hours (+/- 6 hours) post-injection. Patients will continue to receive doses of unlabeled MM-302 plus trastuzumab every 3 weeks until clinical or radiographic disease progression (in brain or systemically) or unacceptable toxicity, whichever occurs soonest. MRI and FDG-PET/CT scans will be performed every 9 weeks to monitor for treatment response and disease progression. | Drug: MM-302<br> <br> * Other names: MM-302 brain study;Drug: Trastuzumab<br> <br> * Other names: Herceptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MM-302 drug penetration into the brain | by Positron emission tomography-magnetic resonance (MR/PET) imaging | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event | In overall cohort NCI CTCAE v.4.0 | 1 year | 
| Overall response rate | By Revised Assessment in Neuro-Oncology (RANO) criteria | 1 year | 
| Overall response rate | By Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria | 1 year | 
| Progession-free survival | In the central nervous system (CNS) | 1 year | 
| Progession-free survival | Systemically | 1 year | 
| CNS response rate | In overall cohort | 1 year | 
| Systemic response rate | In overall cohort | 1 year | 
| Adverse Event | Treatment with radioactive MM-302 | 1 year | 
| Adverse Event | Treatment with MM-302 and trastuzumab | 1 year |