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