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
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).
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.
4. Age greater than or equal to (>/=) 18
5. Male and Female
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Absolute neutrophil count (ANC) count >/= 1,500/cubic millimeters (mm^3) without the
use of growth factors in the past 7 days;
8. Platelet count >=100,000/mm^3 without platelet transfusion in the past 5 days;
9. Hemoglobin >=9 grams per deciliter (g/dL) (packed red blood cell transfusion is
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.
13. Participants with well-controlled asthma (for example Use of rescue medications <2
times/week over the last 12 months) or Chronis Obstructive Pulmonary Disease (COPD)
(for example no exacerbations over the prior 3 months) may be enrolled.
14. Creatinine <1.5 times normal, or creatinine clearance greater than (>) 45 milliliters
per minute (mL/min).
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
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.
17. At least 4 weeks since prior surgery and recovered in opinion of investigator.
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.
Participants meeting any of the following criteria will not be eligible for enrollment:
1. 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.
2. 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
3. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
virus (HCV) positivity.
4. History of solid organ transplantation.
5. Known or suspected allergy or immediate or delayed hypersensitivity to PTC596 or
dacarbazine or any agent given in this study.
6. Bowel obstruction, malabsorption, or other contraindication to oral medication.
7. Gastrointestinal disease or other condition that could affect absorption.
8. Active peptic ulcer disease.
9. Inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis.
10. Any condition that impairs participant's ability to swallow oral medications.
11. Serious non-healing wound, ulcer, or bone fractures.
12. 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.
13. Mucosal or internal bleeding.
14. Concomitant strong CYP1A2 inhibitors (like selective serotonin reuptake inhibitor
[SSRI] agents fluvoxamine and fluoxetine) should be avoided. CYP1A2 inhibitors may
inhibit the conversion of dacarbazine to its active metabolite and may increase the
exposure of PTC596.
15. 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.
16. Known coagulopathy or bleeding diathesis. Participants on anti-coagulation should be
monitored closely and International Normalized Ratio (INR) within normal range.
17. 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.
18. 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.