Study of Liposomal Annamycin for the Treatment of Subjects With Soft-Tissue Sarcomas (STS) With Pulmonary Metastases

Study Overview
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Brief Summary
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This is a multi-center, open-label, single-arm study that in Phase 1b will determine the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) and safety of L-Annamycin and in Phase 2 will explore the efficacy of L- Annamycin as a single agent for the treatment of subjects with STS with lung metastases for which chemotherapy is considered appropriate.

Official Title
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Phase 1B/2 Study Of Liposomal Annamycin (L-Annamycin) In Subjects With Previously Treated Soft-Tissue Sarcomas With Pulmonary Metastases

Conditions
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Sarcoma,Soft Tissue, Pulmonary Metastasis

Intervention / Treatment
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* Drug: Liposomal Annamycin (L-Annamycin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subject has a pathologically confirmed diagnosis of STS. The subject must have radiographically measurable disease in the lung that can be assessed using RECIST v.1.1 (defined as the presence of at least one lesion on MRI or CT scan that can be accurately measured with the longest diameter in at least one dimension of ≥10 mm). Subjects with extra-pulmonary disease are eligible. The subject has documented lung metastases that are considerable eligible for chemotherapy and not eligible for potentially curative surgical resection of pulmonary-only metastatic disease. The subject had prior therapy for their disease and has shown progression of disease prior to study entry. If the subject received prior anthracycline therapy, they must have received a cumulative dose of ≤ 450 mg/m2. The subject has an estimated life expectancy of greater than 3 months. The subject has an ECOG performance status ≤2. The subject is ≥18 years old at the time of signing informed consent. At least 2 weeks must have passed following treatment for subject's disease with chemotherapy, investigational therapy, targeted agents, biological agents, immune modulators, or radiotherapy. Any toxicities must have resolved to ≤ grade 1 or previous baseline levels no more than 4 weeks after completing therapy (except alopecia and polyneuropathy). The subject must have the following adequate laboratory results within 72 hours of starting protocol therapy: Absolute neutrophil count ≥ 1500/mL Platelet count ≥100,000/mL Hemoglobin ≥ 8.0 g/dL Adequate renal function (The Cockcroft-Gault equation will be used to estimate creatinine clearance. CrCl (male) = ([140-age] x weight in kg) / (serum creatinine x 72) CrCl (female) = ([140-age] x weight in kg) / (serum creatinine x 72) x .85 Bilirubin ≤1.5 x ULN (unless due to Gilbert's syndrome) Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and/or alanine aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 × ULN (≤ 5 x ULN in subjects with liver metastases) The subject is able to understand and sign the informed consent document, can communicate with the Investigator, and can understand and comply with the requirements of the protocol. All subjects must agree to practice effective contraception during the entire study period and after discontinuing study drug, unless documentation of infertility exists. Sexually active, fertile women must agree to use 2 effective forms of contraception (abstinence, intrauterine device, oral contraceptive, or double barrier device) from the time of informed consent and until at least 6 months after discontinuing study drug Sexually active men and their sexual partners must agree to use effective contraceptive methods from the time of informed consent until at least 6 months after discontinuing study drug Exclusion Criteria: The subject has any uncontrolled intercurrent illness that, in the opinion of the Investigator, would place the subject at unacceptable risk to participate in the study. Examples include, but are not limited to: Ongoing or active infection Known positive status for human immunodeficiency virus (HIV) or active hepatitis B or C Cirrhosis Psychiatric illness/social situations that would limit compliance with study requirements The subject has any of the following cardiotoxicities: Left ventricular ejection fraction (LVEF) <50% Valvular heart disease Severe hypertension not controlled by medical therapy New York Heart Association classification of 3 or 4 (Appendix B) Recent (≤ 6 months) myocardial infarction Unstable angina Symptomatic congestive heart failure Baseline QT/QTc interval >480 msec History of additional risk factors for torsade des pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) Use of concomitant medications that significantly prolong the QT/QTc interval The subject is pregnant (must have negative serum or urine pregnancy test) or lactating. The subject has a known allergy to study drug, L-Annamycin, or excipients. The subject is required to use moderate or strong inhibitors and inducers of Cytochrome P450 family enzymes CYP3A and CYP2B and transporters that cannot be held 3 days before treatment and on the day of treatment (Appendix E). The subject is unable to comply with the safety monitoring requirements.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liposomal Annamycin (L-Annamycin)<br> | Drug: Liposomal Annamycin (L-Annamycin)<br>* 2-hour intravenous (IV) infusion of L-Annamycin on Day 1 followed by 20 days off of study drug (i.e., 1 treatment cycle= 21 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | Number of patients with a dose limiting toxicity (DLT) at each dose evaluated | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of L-Annamycin | Determine preliminary efficacy of L-Annamycin as per revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) | At the end of every other treatment cycle ( each cycle is 21 days) | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of L-Annamycin | Determine pharmacokinetics of L-Annamycin and its metabolite, annamycinol as measured by AUC | Cycle 1 Day 1 ( each cycle is 21 days) |