Assessing the Combination of Durvalumab (MEDI4736) and Trabectedin in Solid Tumors

This study will include dose escalation and dose expansion phases.

In the dose escalation portion, patients with advanced cancer will be enrolled and treated
with Durvalumab and Trabectedin. Durvalumab will be administered at the same dose in each
dose escalation cohort, while the dose of Trabectedin will be progressively increased in
different cohorts until the safest dose of the combination is determined.

In the dose expansion portion patients will be treated with the safest dose of the study
drugs determined during the dose escalation phase. There will be two separate groups of
patients treated at this dose to evaluate anti-tumor efficacy of the combination. One group
will consist of non-small-cell lung cancer patients previously treated with PD-1 or PD-L1
inhibitors and another group will consist of an immunotherapy naive group of patients. This
immunotherapy naive group of patients will include sarcoma and another tumor type, this other
tumor type will be determined based on anti-tumor efficacy seen during the dose escalation.

The study drugs will be given intravenously every 3 weeks. Treatment will continue for up to
one year or until disease progression.

Inclusion Criteria at Screening and C1D1:

1. Ability to understand and the willingness to sign a written informed consent document

2. Written informed consent and any locally-required authorization (e.g., HIPAA in the
USA) obtained from the patient prior to performing any protocol-related procedures,
including screening evaluations

3. AGE ≥ 18

4. Alkaline phosphatase (ALP) level ≤ upper limit of normal (ULN)

5. Aspartate aminotransferase (AST) and alanine amino transferase (ALT) ≤ ULN

6. Bilirubin ≤ ULN, if total bilirubin is > ULN, measure direct/indirect bilirubin to
evaluate for Gilbert's Syndrome (if direct bilirubin is within normal range, subject
may be eligible)

7. Albumin ≥ 2.5 g/dL

8. CPK ≤ 2.5 xULN

9. Body weight > 30 kg

10. ECOG performance status 0-1

11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).

- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).

12. Evaluable disease for dose escalation, measurable disease per RECIST 1.1 for dose
expansions

13. Hemoglobin ≥ 9 g/dL

14. Neutrophil count ≥ 1.5 x 10^9/L

15. Platelets ≥ 100 x 10^9/L

16. Measured creatinine clearance (CL) ≥ 50 mL/min or Calculated creatinine CL≥ 50 mL/min
by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
collection for determination of creatinine clearance:

This calculation will be performed by a member of the clinical study team

Males:

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) / 72 x serum creatinine (mg/dL)

Females:

Creatinine CL (mL/min) = [Weight (kg) x (140 - Age)/72 x serum creatinine (mg/dL)] x
0.85

17. Any advanced unresectable/stage IV solid tumor with exception of primary CNS
malignancy is permitted.

18. Enrolled patients may be candidates for standard of care therapy with trabectedin or
second line/subsequent line treatment for advanced disease with PD-1/PD-L1 inhibitor
monotherapy. Otherwise they should have no standard of care option available or be
felt appropriate for a phase I clinical trial in the opinion of the treating
investigator. Prior PD-1/PD-L1 exposure is not an exclusion criteria.

19. For the expansion cohort of NSCLC patients previously treated with and having
progressed on immunotherapy patients must have no standard of care option available or
have contraindications to such treatment (including those who decline such treatment).

20. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and exams including follow up.

Exclusion Criteria:

1. Strong inhibitors or inducers of cytochrome P450 3A (washout from prior use of such
agents before C1D1 must exceed 21 days).

2. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.

3. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies
or other investigational product) ≤ 28 days. However, if a therapy has a short
half-life, then patients may participate if they received prior treatment ≤ 28 days
before starting study treatment with approval from the PI and AstraZeneca/Janssen.
Acceptable washout periods include:

1. 3-14 days for prior TKI depending on half-life

2. 14-28 days for prior PD-1 or PD-L1 inhibitor treatment depending on the frequency
of administration (i.e., wait one full cycle of prior PD-1 axis inhibition before
starting study drugs)

4. Therapeutic radiation within 6 weeks of cycle 1 day 1. Exceptions are palliative
radiation and/or stereotactic radiation to non-target lesions.

5. If received prior immunotherapy must not have experienced one of the following:

- A toxicity that led to permanent discontinuation of prior immunotherapy

- All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.

- Must not have experienced a ≥Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably
maintained on appropriate replacement therapy and are asymptomatic.

- Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE and must not have experienced
recurrence of an AE if re-challenged.

6. Prior treatment with trabectedin or trabectedin analog

7. History of another malignancy except for:

- Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of study drugs and of low potential risk for recurrence

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease

- Adequately treated carcinoma in situ without evidence of disease e.g., cervical
cancer in situ

8. Mean QT interval corrected for heart rate (QTc) > 450 ms for males or > 470 msec for
females calculated from 3 electrocardiograms (ECGs) using Fredericia's Formula (within
at least 15 minutes, at least 5 minutes apart)

9. Current or prior use of systemic immunosuppressive medication within 28 days before
the first dose of durvalumab + trabectedin, with the exception of systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion:

- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)

10. Any unresolved toxicity (non-immune mediated) NCI CTCAE Grade ≥ 2 from previous
anticancer therapy with the exception of alopecia

- However, patients with irreversible toxicity not reasonably expected to be
exacerbated by the treatment with durvalumab + trabectedin may be included only after
consultation with the Principal Investigator.

11. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of study drugs. Note: Local surgery of isolated lesions for palliative
intent is acceptable.

12. History of allogenic organ transplantation (both solid organ and bone marrow)

13. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criterion:

- Patients with vitiligo or alopecia

- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement

- Any chronic skin condition that does not require systemic therapy

- Patients without active disease in the last 5 years may be included, but only
after consultation with the PI

- Patients with celiac disease controlled by diet alone

14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirements, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.

15. Cirrhosis of any Child Pugh class

16. Left ventricular ejection fraction less than 50%

17. History of pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis,
idiopathic pneumonitis or evidence of symptomatic interstitial lung disease on chest
computed tomography (CT).

18. History of leptomeningeal carcinomatosis

19. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis
that meets RECIST criteria identified either on the baseline brain imaging obtained
during the screening period or identified prior to signing the informed consent form
(ICF). Patients whose brain metastases have been treated may participate provided they
show radiographic stability (defined as 2 brain images, both of which are obtained
after treatment to the brain metastases. These imaging scans should both be obtained
at least four weeks apart and show no evidence of intracranial progression). In
addition, any neurologic symptoms that developed either as a result of the brain
metastases or their treatment must have resolved or be stable either, without the use
of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its
equivalent and not requiring anticonvulsants for at least 14 days prior to the start
of treatment.

20. History of active primary immunodeficiency

21. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (HBsAg positive), hepatitis C, or human immunodeficiency
virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection
(defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HbsAg)
are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.

22. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drugs. Note: Patients, if enrolled, should not receive live vaccine whilst receiving
treatment with study drugs and up to 90 days after the last dose of study drugs.

23. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control (as
defined in section 7.1 of protocol) from screening to 180 days after receipt of the
last dose of study drugs.

24. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

25. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
study regardless of treatment arm assignment.

26. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.