Clinical Trials /

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

NCT03761095

Description:

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).

Related Conditions:
  • Leiomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of PTC596 in Combination With Dacarbazine in Participants With Advanced Leiomyosarcoma (LMS)
  • Official Title: A Phase 1B Study of PTC596 in Combination With Dacarbazine in Patients With Locally Recurrent, Unresectable or Metastatic Relapsed/Refractory Leiomyosarcoma

Clinical Trial IDs

  • ORG STUDY ID: PTC596-ONC-007-LMS
  • NCT ID: NCT03761095

Conditions

  • Leiomyosarcoma

Interventions

DrugSynonymsArms
PTC596PTC596 and Dacarbazine
DacarbazineDTICPTC596 and Dacarbazine

Purpose

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

Trial Arms

NameTypeDescriptionInterventions
PTC596 and DacarbazineExperimentalParticipants 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).
  • PTC596
  • Dacarbazine

Eligibility 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.

          -  Histological or cytological confirmation of LMS arising at any anatomic site.

          -  Advanced (metastatic) or locally advanced unresectable disease.

          -  Ineligible for other high-priority national or institutional study.

          -  Measurable disease per RECIST v1.1 criteria.

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

          -  Hematopoietic: Absolute neutrophil count (ANC) count greater than or equal to (>=)
             1,500/cubic millimeters (mm^3); Platelet count >=100,000/mm^3; Hemoglobin >=9 grams
             per decileter (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.

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

          -  Toxicity from prior therapies recovered to Grade lesser than or equal to (<=) 1 or
             participant's baseline.

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

          -  At least 4 weeks since prior radiotherapy.

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

          -  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.

        Exclusion Criteria:

          -  Received any systemic anticancer therapy including investigational agents <=3 weeks
             (or <=5 half-lives of the drug, whichever is longer) prior to registration.

          -  Co-existing active infection or any co-existing medical condition likely to interfere
             with study procedures, including: 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.

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

          -  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.

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

          -  Major surgery, open biopsy or significant traumatic injury within 28 days of
             registration for protocol therapy.

          -  Mucosal or internal bleeding.

          -  Severe pulmonary problems generally defined by need for medical intervention (for
             example, oxygen, medications) and/or limiting activities of daily living (generally
             Common Terminology Criteria for Adverse Events [CTCAE] Grade 2) or shortness of breath
             with limited exertion. Pulmonary conditions include, for example, chronic obstructive
             pulmonary disease (COPD), asthma, and hemi-pneumectomy.

          -  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.

          -  Prior malignancy except curatively treated carcinoma in situ of the cervix or skin
             cancer.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:MTD of PTC596 in Combination With Dacarbazine
Time Frame:First 2 cycles of treatment (6 weeks)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:Objective Response is defined as confirmed best response of complete response (CR) or partial response (PR).
Measure: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)
Safety Issue:
Description:Time to response is defined as the first time either PR or CR occurs.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:Best overall response is defined as CR, PR and stable disease (SD).
Measure: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)
Safety Issue:
Description:OS is defined as the time from the first dose of study drug to the date of death from any cause.
Measure: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
Safety Issue:
Description:Pharmacokinetic (PK) variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.
Measure: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
Safety Issue:
Description:PK variables will be calculated from the plasma concentration data using standard compartmental or non-compartmental methods, as appropriate for the data.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PTC Therapeutics

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