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A Study of PTC596 in Combination With Dacarbazine in Participants With Advanced Leiomyosarcoma (LMS)

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ClinicalTrials.gov Identifier: NCT03761095
Recruitment Status : Recruiting
First Posted : December 3, 2018
Last Update Posted : November 28, 2019
Sponsor:
Information provided by (Responsible Party):
PTC Therapeutics

Brief Summary:

The primary objective of this study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PTC596 in combination with dacarbazine for the treatment of advanced LMS and determine the overall safety profile of PTC596 in combination with dacarbazine.

This study will employ the time-to-event continual reassessment method (TITE-CRM) for dose finding. Treatment will be initiated at dose level 2 (DL2) (Dacarbazine 1000 milligrams per square meter [mg/m^2] intravenously (IV) every 21 days in combination with PTC596 200 milligrams [mg] orally twice weekly) for the first participant. This dose level represents the investigator's best assessment of the MTD based on available toxicity data for both agents. For subsequent participants, the dose level at which treatment is initiated will be selected based on the TITE-CRM using the most up to date dose-limiting toxicity (DLT) information from all participants previously treated.

Treatment will continue for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason (study intervention discontinuation and participant discontinuation/withdrawal).


Condition or disease Intervention/treatment Phase
Leiomyosarcoma Drug: PTC596 Drug: Dacarbazine Phase 1

Expanded Access : PTC Therapeutics has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B Study of PTC596 in Combination With Dacarbazine in Patients With Locally Recurrent, Unresectable or Metastatic Relapsed/Refractory Leiomyosarcoma
Actual Study Start Date : March 13, 2019
Estimated Primary Completion Date : December 20, 2020
Estimated Study Completion Date : December 20, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Dacarbazine

Arm Intervention/treatment
Experimental: PTC596 and Dacarbazine
Participants will receive PTC596 orally twice weekly in combination with dacarbazine IV once every 21 days. First participant will receive dacarbazine 1000 mg/m^2 IV every 21 days in combination with PTC596 200 mg tablet orally twice weekly. For subsequent participants, the dose level at which treatment is initiated will be selected based on the TITE-CRM using the most up to date dose DLT information from all participants previously treated. Treatment will continue for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason (study intervention discontinuation and participant discontinuation/withdrawal).
Drug: PTC596
PTC596 will be administered as per the dose and schedule specified in the arm.

Drug: Dacarbazine
Dacarbazine will be administered as per the dose and schedule specified in the arm.
Other Name: DTIC




Primary Outcome Measures :
  1. MTD and RP2D of PTC596 in Combination With Dacarbazine [ Time Frame: First 2 cycles of treatment (6 weeks) ]
    MTD will be determined using the TITE-CRM for dose-finding. MTD is defined as the dose associated with a target probability of DLT of 0.25.

  2. Number of Participants With Adverse Events [ Time Frame: From screening until end of study (up to approximately 1.5 years) ]

Secondary Outcome Measures :
  1. Objective Response Rate (ORR) (Percentage of Participants With Objective Response) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: From Baseline until the date of objectively documented progression per RECIST v1.1 or the date of initiation of subsequent therapy or palliative local therapy, whichever occurs first (up to approximately 1.5 years) ]
    Objective Response is defined as confirmed best response of complete response (CR) or partial response (PR).

  2. Time to Response as Determined by the Investigator Using RECIST v1.1 [ Time Frame: From Baseline until the date of first occurrence of CR or PR (up to approximately 1.5 years) ]
    Time to response is defined as the first time either PR or CR occurs.

  3. Duration of Response (DOR) [ Time Frame: Time from the date of first confirmed response to the date of the first documented tumor progression or death due to any cause, whichever occurs first (up to approximately 1.5 years) ]
    DOR is defined as the time from the date of first confirmed response to the date of the first documented tumor progression (per RECIST v1.1) or death due to any cause, whichever occurs first.

  4. Progression-Free Survival (PFS) [ Time Frame: Time from the first dose of study drug to the date of the first documented tumor progression or death due to any cause, whichever occurs first (up to approximately 1.5 years) ]
    PFS is defined as the time from the first dose of study drug to the date of the first documented tumor progression as determined by the investigator using RECIST v1.1 or death due to any cause, whichever occurs first.

  5. Best Overall Response Rate (Disease Control Rate) (Percentage of Participants With Best Overall Response) [ Time Frame: From Baseline until the date of objectively documented progression per RECIST v1.1 or the date of initiation of subsequent therapy or palliative local therapy, whichever occurs first (up to approximately 1.5 years) ]
    Best overall response is defined as CR, PR and stable disease (SD).

  6. Overall Survival (OS) [ Time Frame: Time from the first dose of study drug to the date of death from any cause (up to approximately 1.5 years) ]
    OS is defined as the time from the first dose of study drug to the date of death from any cause.

  7. Maximum Observed Plasma Concentration (Cmax) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (5-amino-imidazole-4-carboxamide [AIC]) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    Pharmacokinetic (PK) variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  8. Time to Reach Maximum Plasma Concentration (Tmax) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  9. Area Under the Plasma Concentration-Time Curve (AUC) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  10. Half-Life (t1/2) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  11. Apparent Clearance (CL/F) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  12. Apparent Volume of Distribution (Vz/F) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

  13. Accumulation Ratio (R) of PTC596, Dacarbazine, and Inactive Metabolite of Dacarbazine (AIC) [ Time Frame: PTC596: Pre-dose; 1, 2, 3, 4, 6, 8, and 24 hours post-dose on Day 8 and Day 22; Dacarbazine: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 and Day 22; AIC: Pre-dose; 0.5, 1.0, 1.25, 1.5, 2, 4, 8, and 24 hours post-dose on Day 1 ]
    PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

- Signed consent of an Institutional Review Board (IRB)-approved informed consent form (ICF) and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information (if appropriate).

- Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

- Disease Status including all of the following:

  1. Histological or cytological confirmation of LMS arising at any anatomic site.
  2. Advanced (metastatic) or locally advanced unresectable disease.
  3. Ineligible for other high-priority national or institutional study.
  4. Measurable disease per RECIST v1.1 criteria.

    Demographics:

    • Age greater than or equal to (>/=) 18
    • Male and Female

    Performance Status:

    - Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

    Hematopoietic:

    - Absolute neutrophil count (ANC) count >/= 1,500/cubic millimeters (mm^3);

    • Platelet count >=100,000/mm^3;
    • Hemoglobin >=9 grams per deciliter (g/dL).

    Hepatic:

    • Bilirubin lesser than (<) upper limit of normal (ULN);
    • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <1.5 times ULN;
    • Participants with liver metastases may be enrolled.

    Pulmonary:

    - Participants with well-controlled asthma (for example Use of rescue medications <2times/week over the last 12 months) or Chronis Obstructive Pulmonary Disease (COPD) (for example no exacerbations over the prior 3 months) may be enrolled.

    Renal:

    - Creatinine <1.5 times normal, or creatinine clearance greater than (>) 45 milliliters per minute (mL/min).

    Prior Therapies:

    - Toxicity from prior therapies recovered to Grade lesser than or equal to (<=) 1 or participant's baseline, except for alopecia. In addition, endocrinopathies associated with prior immunotherapy based treatments which are well controlled on replacement medication are not exclusionary

    Chemotherapy:

    - Up to 4 prior systemic oncology therapy regimens for metastatic, locally recurrent, or unresectable LMS.

    Surgery:

    • At least 4 weeks since prior radiotherapy.
    • At least 4 weeks since prior surgery and recovered in opinion of investigator

    Other:

    • Capable of swallowing oral medication.
    • Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy.
    • Males and females of childbearing potential must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 90 days after treatment discontinuation. Note: The Definition of effective contraception will be based on the judgement of the Principal Investigator (PI) or Designee.

    Exclusion Criteria:

    - Received any systemic anticancer therapy including investigational agents <=3 weeks (or <=5 half-lives of the drug, whichever is longer) prior to initiation of study treatment. Additionally, Participants may have not received radiation </= 3 weeks prior to initiation of study treatment.

    • Co-existing active infection or any co-existing medical condition likely to interfere with study procedures, including: a) Significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for anti-arrhythmic therapy, or evidence of ischemia on electrocardiogram (ECG), marked baseline prolongation of QT/QTc (corrected QT interval) interval, for example, repeated demonstration of a QTc interval >500 milliseconds (msec) (Long QT Syndrome [congenital]).
    • Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) positivity.
    • History of solid organ transplantation.

    Therapeutics:

    - Known or suspected allergy or immediate or delayed hypersensitivity to PTC596 or dacarbazine or any agent given in this study.

    Gastrointestinal:

    • Bowel obstruction, malabsorption, or other contraindication to oral medication.
    • Gastrointestinal disease or other condition that could affect absorption.
    • Active peptic ulcer disease.
    • Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis.
    • Any condition that impairs participant's ability to swallow oral medications.

    Wounds /Surgery:

    - Serious non-healing wound, ulcer, or bone fractures.

    • Major surgery, open biopsy or significant traumatic injury which has not recovered in the opinion of the investigator, within 28 days of registration for protocol therapy.
    • Mucosal or internal bleeding.

    Concomitant Medications:

    - At baseline, no drugs that are substrates, inhibitors, or inducers of cytochrome P1A2 (CYP1A2) or moderate/strong cytochrome P (CYP) inducers such as St. John's Wort, rifampicin, phenytoin, etc.

    Other:

    - Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer or adequately treated cervical carcinoma in situ) during the 5 years prior to initiation. Cancer treated with curative intent more than 5 years previously and without evidence of recurrence is not an exclusion.

    - Known coagulopathy or bleeding diathesis.

    - Prior or ongoing clinically significant illness, medical or psychiatric condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the participant, or alter the absorption, distribution, metabolism, or excretion of the study drugs, or could impair the assessment of study results.

    - History of brain metastases or leptomeningeal disease at any time in participant's history, including treated central nervous system (CNS) disease which is clinically and radiographically stable.


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): NCT03761095


Contacts
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Contact: Senior VP Corporate Relations 1-866-562-4620 medinfo@ptcbio.com
Contact: Medical Information 1-866-562-4620 medinfo@ptcbio.com

Locations
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United States, Florida
Mayo Clinic Florida Recruiting
Jacksonville, Florida, United States, 32204
Contact: Dr. Steven Attia    904-953-7292    Attia.Steven@mayo.edu   
Principal Investigator: Steven Attia         
United States, Maryland
John Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Christian Meyer    410-502-9940    Cmeyer13@jhmi.edu   
United States, Massachusetts
Dana-Farber Cancer Institute Withdrawn
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University Medical Campus Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Dr. Brian Van Tine    314-662-6532    bvantine@wustl.edu   
Contact: Cheryl Callahan    314-286-2584    callahanc@dom.wustl.edu   
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Dr. Mathew Ingham       mi2337@cumc.columbia.edu   
Sponsors and Collaborators
PTC Therapeutics
Investigators
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Principal Investigator: Matthew Ingham Columbia University
Principal Investigator: Steven Attia Mayo Clinic
Principal Investigator: Suzanne George Dana-Farber Cancer Institute
Principal Investigator: Brian Van Tine Washington University Medical Campus
Principal Investigator: Christian Meyer Johns Hopkins University

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Responsible Party: PTC Therapeutics
ClinicalTrials.gov Identifier: NCT03761095     History of Changes
Other Study ID Numbers: PTC596-ONC-007-LMS
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: November 28, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leiomyosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma