A Phase II Multi-Strata Study of PM01183 as a Single Agent or in Combination With Conventional Chemotherapy in Metastatic and/or Unresectable Sarcomas

Study Overview
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Brief Summary
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This research study is investigating a drug called PM01183 alone and in combination with chemotherapy drugs called gemcitabine or doxorubicin as a possible treatment for metastatic or unresectable Sarcoma.

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. PM01183 is a new drug that is believed to bind DNA cause double strands of DNA to break. This drug has been studied in previous research studies, and these suggest that it may slow or stop the growth of cancers. The FDA (the U.S. Food and Drug Administration) has not approved PM01183 as a treatment for any disease. In this research study, the investigators are trying to assess the effects, good or bad, that PM01183, administered either alone or in combination with gemcitabine or doxorubicin has on metastatic or unresectable sarcoma.

Official Title
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A Phase II Multi-Strata Study of PM01183 as a Single Agent or in Combination With Conventional Chemotherapy in Metastatic and/or Unresectable Sarcomas

Conditions
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Metastatic Sarcoma

Intervention / Treatment
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* Drug: PM01183
* Drug: Doxorubicin
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have pathologically confirmed soft-tissue sarcoma, which is metastatic or unresectable, sarcoma with no curative multimodality options Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. No more than two prior lines of chemotherapy for metastatic sarcoma are allowed; Neo-adjuvant/adjuvant chemotherapy with definitive therapy (radiation, surgery or radiation and surgery) will not be counted as one of these prior lines of therapy. Age ≥ 18 and ≤ 75 years. Eastern Cooperative Oncology Group performance status ≤1 (see Appendix A) Life expectancy of greater than 3 months Participants must have normal organ and marrow function as defined below: Hemoglobin ≥ 9 g/dl absolute neutrophil count ≥ 1,500/mcL platelets ≥ 100,000/mcL total bilirubin ≤ 1.5 X ULN AST(SGOT)/ALT(SGPT) ≤3 X ULN (including patients with liver metastases) creatinine ≤1.5 X ULN CPK < 2.5 X ULN Albumin ≥ 3 g/dl Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to receiving study agents. For patients in stratum A, an echocardiogram or multiple gated acquisition scan (MUGA) demonstrating left ventricular ejection fraction > 50% is required within 30 days prior to study drug administration. Participants must be willing and able to comply with the study scheduled visits, laboratory tests, and other procedures outlined in the protocol. Pre-menopausal women must have a negative pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for at least six weeks after treatment discontinuation. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant, double barrier and/or complete abstinence (non-periodic). Washout period prior to Day 1 Cycle 1: ≥ 3 weeks since last chemotherapy or therapeutic radiation therapy (RT) ≥ 4 weeks or 3 half-lives since prior antibody-based therapy, whichever is shorter ≥ 2 weeks since any oral anti-neoplastic or oral investigational agent Resolution of treatment-related toxicity to ≤ grade 1; alopecia and cutaneous toxicity are allowed ≤ grade 2. ≥1 week since palliative RT Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior exposure to PM01183 Patients who have received trabectedin (Yondelis, ET-743) or participated in the phase III clinical study of trabectedin NCT01343277 previously will not be eligible. For stratum A, patients must not have received prior anthracycline-based therapy (prior treatment with non-anthracyclines is permitted). For stratum B patients must have received prior anthracycline-based therapy (or have a contraindication to receiving this treatment) and must not have received prior gemcitabine For stratum C, patients must have received prior anthracycline or gemcitabine-based therapy, or had a contraindication to either or both Prior radiation treatment of >45 Gy to the pelvis Previously untreated Ewing Sarcoma and rhabdomyosarcoma Non-soft tissue sarcomas, such as osteosarcoma and chondrosarcoma are excluded Participants who are receiving any other investigational agents. Active hepatopathy of any origin including active hepatitis B and hepatitis C Participants with known uncontrolled brain metastases will be excluded from this clinical. History of allergic reactions attributed to compounds of similar chemical or biologic composition to PM01183 or trabectedin (Yondelis, ET-743). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, chronic indwelling drains, history of interstitial pneumonitis or pulmonary fibrosis or psychiatric illness/social situations that would limit compliance with study requirements. Actively breastfeeding women unless it is interrupted during treatment and at least 6 weeks after treatment discontinuation. Known myopathy or persistent CPK elevations >2.5 ULN in two different determinations performed one week apart. Immunocompromised patients, including those with HIV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PM01183 and Doxorubicin<br>Anthracycline-naïve patients will receive combination of PM01183 and Doxorubicin per cycle. PM01183 predetermined dose daily via IV per cycle Doxorubicin predetermined dose daily via IV per cycle | Drug: PM01183<br> <br> * Other names: lurbinectedin;Drug: Doxorubicin<br> <br> * Other names: Hydroxydoxorubicin Hydrochloride;|
| Experimental: PM01183 and Gemcitabine<br>Prior anthracycline exposure and without prior gemcitabine exposure PM01183 predetermined dose given twice via IV per cycle Gemcitabine predetermined dose given twice via IV per cycle | Drug: PM01183<br> <br> * Other names: lurbinectedin;Drug: Gemcitabine<br> <br> * Other names: Gemzar;|
| Experimental: Single Agent PM01183<br>Patients who have received at least both prior anthracycline and prior gemcitabine -PM01183 predetermined dose once via IV per cycle | Drug: PM01183<br> <br> * Other names: lurbinectedin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate | The number of participants that achieved either Stable Disease (SD) or a Partial Response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at 24 weeks. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The overall response rate is the number of participants that achieved either Stable Disease (SD), a Partial Response (PR), or a Complete Response (CR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The overall response rate is the best response recorded from the start of treatment until disease progression/recurrence. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Every 6 weeks for the first 8 cycles (cycle is 21 days) and then every 9 weeks thereafter until disease progression | 
| Treatment Related Serious Adverse Events | Summary of the serious adverse events (SAE) experienced by participants that were deemed to be at least possibly related to PM01183 when administered alone or with Doxorubicin or Gemcitabine. Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE v4). | From the start of treatment until 30 days after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Sarcoma, Unresectable Sarcoma, PM01183