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 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).

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:

          1. 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).

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

          3. 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:

          4. Age greater than or equal to (>/=) 18

          5. Male and Female

             Performance Status:

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

             Hematopoietic:

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

          8. Platelet count >=100,000/mm^3;

          9. Hemoglobin >=9 grams per deciliter (g/dL).

             Hepatic:

         10. Bilirubin lesser than (<) upper limit of normal (ULN);

         11. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <1.5 times ULN;

         12. Participants with liver metastases may be enrolled.

             Pulmonary:

         13. 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:

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

             Prior Therapies:

         15. 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

         16. Chemotherapy:

             a. Up to and inclusive of 4 prior systemic cytotoxic oncology therapy regimens for
             metastatic, locally recurrent, or unresectable LMS. Note: prior treatment with
             non-cytotoxic therapy regimens (for example targeted therapies, hormonal therapies, or
             tyrosine kinase inhibitors) are not considered cytotoxic oncology therapies.

             Surgery:

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

             Other:

         18. Capable of swallowing oral medication.

         19. Females of childbearing potential must have a negative pregnancy test within 7 days
             prior to being registered for protocol therapy.

         20. 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:

             Participants meeting any of the following criteria will not be eligible for
             enrollment:

         21. Received any systemic anticancer therapy including investigational agents <=3 weeks
             prior to initiation of study treatment. Additionally, Participants may have not
             received radiation </= 3 weeks prior to initiation of study treatment.

         22. 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]).

         23. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
             virus (HCV) positivity.

         24. History of solid organ transplantation.

             Therapeutics:

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

             Gastrointestinal:

         26. Bowel obstruction, malabsorption, or other contraindication to oral medication.

         27. Gastrointestinal disease or other condition that could affect absorption.

         28. Active peptic ulcer disease.

         29. Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
             diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis.

         30. Any condition that impairs participant's ability to swallow oral medications.

             Wounds /Surgery:

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

         32. 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.

         33. Mucosal or internal bleeding.

             Concomitant Medications:

         34. Concomitant use of strong inducers of CYP3A4 (for example phenytoin and rifampin)
             should be avoided. There are no strong or moderate inducers of CYP1A2. The
             coadministration of fluvoxamine (an SSRI), as a strong inhibitor of CYP1A2, should not
             be used and an alternative agent selected. Fluvoxamine has the potential to inhibit
             the conversion of dacarbazine to its active metabolite. Note also that flovoxamine may
             increase the exposure to PTC596 which could enhance the neutropenic effects of PTC596.

             Other:

         35. 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.

         36. Known coagulopathy or bleeding diathesis.

         37. 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.

         38. 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 and RP2D 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: Predose (within 1 hour[hr]); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8,Cycle 2 Day 2; Dacarbazine and AIC: Predose(within 1hr); 0.5,1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1,Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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: Predose (within 1 hr); 1,2,3,4,6,8,24 hrs postdose on Cycle 1 Day 8, Cycle 2 Day 2; Dacarbazine and AIC: Predose (within 1hr); 0.5, 1 hr post start of infusion; 0.25,0.5,1,3,7,23 hrs postdose on Cycle 1 Day 1, Cycle 2 Day 1 (each cycle=21 days)
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

Last Updated

December 19, 2020