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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Sarcoma
• Intervention / Treatment: Drug: Gemcitabine; Drug: Doxorubicin; Drug: PM01183

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: PM01183 and Doxorubicin; 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: Doxorubicin; Other Names: Adriamycin; Hydroxydaunomycin Hydrochloride; Hydroxydoxorubicin Hydrochloride; Drug: PM01183; Other Names: lurbinectedin
EXPERIMENTAL: PM01183 and Gemcitabine; 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: Gemcitabine; Other Names: Gemzar; Drug: PM01183; Other Names: lurbinectedin
EXPERIMENTAL: Single Agent PM01183; Patients who have received at least both prior anthracycline and prior gemcitabine -PM01183 predetermined dose once via IV per cycle	Drug: PM01183; Other Names: lurbinectedin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Dana-Farber Cancer Institute; PharmaMar
• Investigators: Principal Investigator: Gregory Cote, MD PhD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Cote GM, Choy E, Chen T, Marino-Enriquez A, Morgan J, Merriam P, Thornton K, Wagner AJ, Nathenson MJ, Demetri G, George S. A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas. Eur J Cancer. 2020 Feb;126:21-32. doi: 10.1016/j.ejca.2019.10.021. Epub 2019 Dec 31.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2015
• Primary Completion (ACTUAL): February 1, 2017
• Study Completion (ACTUAL): April 1, 2019

Study Registration Dates

• First Submitted: May 15, 2015
• First Submitted That Met QC Criteria: May 15, 2015
• First Posted (ESTIMATE): May 19, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 3, 2021
• Last Update Submitted That Met QC Criteria: February 9, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: PM01183; Metastatic Sarcoma; Unresectable Sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Gemcitabine; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: 15-083