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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

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ClinicalTrials.gov Identifier: NCT02448537
Recruitment Status : Active, not recruiting
First Posted : May 19, 2015
Results First Posted : March 5, 2018
Last Update Posted : August 13, 2018
Sponsor:
Collaborators:
Dana-Farber Cancer Institute
PharmaMar
Information provided by (Responsible Party):
Gregory Cote, Massachusetts General Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Sarcoma Drug: PM01183 Drug: Doxorubicin Drug: Gemcitabine Phase 2

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  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Multi-Strata Study of PM01183 as a Single Agent or in Combination With Conventional Chemotherapy in Metastatic and/or Unresectable Sarcomas
Actual Study Start Date : August 2015
Actual Primary Completion Date : February 2017
Estimated Study Completion Date : February 2021


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: PM01183
Other Name: lurbinectedin

Drug: Doxorubicin
Other Names:
  • Hydroxydaunomycin Hydrochloride
  • Adriamycin
  • Hydroxydoxorubicin Hydrochloride

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: PM01183
Other Name: lurbinectedin

Drug: Gemcitabine
Other Name: Gemzar

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 Name: lurbinectedin




Primary Outcome Measures :
  1. Disease Control Rate [ Time Frame: 24 Weeks ]

    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.


Secondary Outcome Measures :
  1. Overall Response Rate [ Time Frame: Every 6 weeks for the first 8 cycles (cycle is 21 days) and then every 9 weeks thereafter until disease progression ]

    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.

  2. Overall Survival Rate [ Time Frame: from the start of treatment until death ]
    Overall survival is measured as the median duration of time from the start of treatment until the time of death.

  3. Treatment Related Serious Adverse Events [ Time Frame: From the start of treatment until 30 days after the end of treatment ]
    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).



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02448537


Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Massachusetts General Hospital
Dana-Farber Cancer Institute
PharmaMar
Investigators
Principal Investigator: Gregory Cote, MD PhD Massachusetts General Hospital
  Study Documents (Full-Text)

Documents provided by Gregory Cote, Massachusetts General Hospital:

Responsible Party: Gregory Cote, MD PhD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT02448537     History of Changes
Other Study ID Numbers: 15-083
First Posted: May 19, 2015    Key Record Dates
Results First Posted: March 5, 2018
Last Update Posted: August 13, 2018
Last Verified: August 2018

Keywords provided by Gregory Cote, Massachusetts General Hospital:
Metastatic Sarcoma
Unresectable Sarcoma
PM01183

Additional relevant MeSH terms:
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Doxorubicin
Liposomal doxorubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors