The primary objective of this study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of unesbulin in combination with dacarbazine for the treatment of advanced LMS and determine the overall safety profile of unesbulin 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 unesbulin 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. To enroll additional participants at the RP2D, the study is amended to include an expansion cohort of up to 12 participants (some of whom could be ongoing participants who reconsent).

Treatment will continue for each participant until evidence of unacceptable toxicity, disease progression, or treatment discontinuation for another reason.

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) 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 allowed).

   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 <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.

    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, with the last dose of prior therapy administered no fewer than 30 days or 5 times the drug half-life prior to screening. 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:

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 [congenital]).

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

4. History of solid organ transplantation.

   Therapeutics:

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

   Gastrointestinal:

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.

    Wounds /Surgery:

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 baseline.

13. Mucosal or internal bleeding.

    Concomitant Medications:

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 unesbulin.

    Other:

15. Prior malignancies other than LMS, that required treatment or have 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.