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

Early Phase 1

Withdrawn

• Conditions: Documented Her2 Overexpression; Advanced Solid Tumor; Brain Metastases; Neurologically Stable
• Interventions: Drug: MM-302; Drug: Trastuzumab

• Registration Number: NCT02735798
• Lead Sponsor: Pamela Munster

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-04
• Study First Submitted: 2016-04-01
• Study First Submitted QC: 2016-04-07
• Study First Posted: 2016-04-13
• Status Verified: 2017-05
• Last Update Submitted: 2017-05-02
• Last Update Posted: 2017-05-04
• Primary Completion: 2017-06
• Study Completion: 2018-06

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm Study - Arm 1	MM-302	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.
Single Arm Study - Arm 1	Trastuzumab	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.

Primary Outcome Measures

Name	Time	Method
MM-302 drug penetration into the brain	3 hours	by Positron emission tomography-magnetic resonance (MR/PET) imaging

Secondary Outcome Measures

Name	Time	Method
Adverse Event	1 year	Treatment with MM-302 and trastuzumab
Adverse event	1 year	In overall cohort NCI CTCAE v.4.0
Overall response rate	1 year	By Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria
Progession-free survival	1 year	Systemically
CNS response rate	1 year	In overall cohort
Systemic response rate	1 year	In overall cohort