Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma

This is a traditional 3+3 phase I trial design to identify the recommended phase II dose
(RP2D) of Trabectedin [T] that can be used in combination with Doxorubicin [D] and Olaratumab
[O] for the treatment of patients with advanced stage or recurrent LMS.

Patients will be treated at an assigned dose level of combination therapy per dose escalation
design.

Inclusion Criteria:

1. Histologically confirmed metastatic, advanced, or recurrent, LMS. Note: Patients
should have tissue, either archival or fresh biopsy, submitted for pathologic review
to confirm diagnosis of LMS. For patients with recurrent disease with disease free
interval greater than six months, a fresh biopsy must be obtained.

2. All patients with recurrent or metastatic LMS deemed unresectable must have measurable
disease as defined by RECIST 1.1.

All patients with advanced LMS may be enrolled after an initial cytoreductive surgery
if there is measurable disease as defined by RECIST 1.1.

3. Life expectancy greater than 3 months.

4. Male or female, age ≥18 years

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

6. Resolution of clinically significant toxic effects of prior surgery, radiotherapy or
systemic anticancer therapy.

7. Patients must not have received prior doxorubicin chemotherapy; only 1 prior
chemotherapy line allowable and must be discontinued at least 4 weeks prior to first
day of study treatment.

8. Patients should be free of active infections requiring antibiotics (with exception of
urinary tract infection).

9. Patients must have adequate organ and marrow function as defined below: Absolute
neutrophil count (ANC) ≥1,500 cells/mm³

- Platelet count ≥100,000/mm³

- Hemoglobin ≥9.0g/dL

- Total bilirubin <1.0 upper limit of normal (ULN)

- Alkaline phosphatase of non-osseous origin ≤ 2.5 x ULN

- Aminotransferase (AST and ALT) ≤ 2.5 x ULN

- Creatinine phosphokinase (CPK) ≤ 2.5 x ULN

- Isotope Dilution Mass Spectrometry (IDMS) creatinine ≤ 1.5 x ULN or creatinine
clearance ≥ 40 mL/min

- Albumin ≤ 3 g/dL*

- *Hypoalbuminemia < 3 g/dL should be considered carefully but in and of itself,
not exclusionary.

10. Women of child-bearing potential (WOCBP) must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation until 3 months for women and 5 months for men
after completion of study drug administration. WOCBP must have a negative serum or
urine test at time of enrollment. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
therapy, and 5 months after completion of study drug administration.

11. Patients must have adequate cardiac function (ejection fraction ≥ 45%) to receive
therapy.

12. Ability to understand the investigational nature, potential risks and benefits of the
research study and to provide valid written informed consent.

Exclusion Criteria:

1. Patients without histologically confirmed LMS

2. Patients without measurable disease by RECIST 1.1 criteria

3. Prior doxorubicin, trabectedin, or olaratumab chemotherapy

4. Patients with an ECOG of 2, 3 or 4 (Appendix C)

5. Patient with known allergies to pegfilgrastim/filgrastim.

6. Patients with known active central nervous system (CNS) metastasis and/or
carcinomatous meningitis.

7. Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
study therapy and during the study.

8. Patients with a known sensitivity to humanized antibodies or sensitivity attributed to
compounds of similar chemical or biological composition to alkylating agents or
anthracyclines.

9. A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480 msec.

10. Patients on combination antiretroviral therapy are ineligible.

11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infections (including viral hepatitis), decompensated cirrhosis or chronic liver
disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
the study requirements.

12. Adults unable to consent, pregnant or nursing women or prisoners.

13. Any serious medical or psychiatric illness/condition likely in the judgment of the
Investigator(s) to interfere or limit compliance with study requirements/treatment.

14. Diagnosis of another primary malignancy within the past 5 years with the exception of
non-melanoma skin cancer.

15. Patients with a prior history of grade 3 capillary leak syndrome (CLS) or with pulmonary involvement.

16. Unwilling to abstain from alcohol ingestion for duration of the study

17. Patients with elevated liver function or bilirubin not meeting criteria for treatment