PaTcH Study: A Phase 2 Study of Trametinib and Hydroxychloroquine in Patients With Metastatic Refractory Pancreatic Cancer

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be eligible for the study:

1. Patients must have pathologically confirmed advanced metastatic pancreaticadenocarcinoma or poorly differentiated pancreatic adenocarcinoma that is amenableto tumour biopsy.

2. Patients have received at least one line of systemic therapy for metastatic diseaseand not be amenable to surgical resection.

3. Patients must have measurable disease by RECIST 1.1 criteria.

4. Age ≥18 years.

5. ECOG performance status ≤ 1

6. Patients must have normal organ and marrow function as defined below:

7. Serum creatinine ≤ 1.5 x ULN.

8. Adequate hepatic function defined by:

• total bilirubin level ≤ 1.5 × ULN,
• an AST, level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN (or, for subjectswith documented metastatic disease to the liver, AST and ALT levels ≤ 5 ×ULN)

3. Hematological eligibility parameters:

• Absolute Neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥100 x109/L
• Hemoglobin ≥ 9 g/dL

7. Ability of subject to understand and the willingness to sign a written informedconsent document.

8. Women of child-bearing potential or sexually active males must agree to use highlyeffective contraceptive measures. This applies from starting treatment until atleast 16 weeks after the last study drug administration. The investigator or adesignated associate is required to advise the patient how to achieve an adequatebirth control. Highly effective contraception is defined in the study as methodsthat achieve a failure rate of less than 1% per year when used consistently andcorrectly. Such methods include:

I. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). II. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable). III. Intrauterine device (IUD). IV. Intrauterine hormone-releasing system (IUS). V. Bilateral tubal occlusion. VI. Successfully vasectomised partner. VII. Sexual abstinence.

Exclusion Criteria:

Patients are excluded from the study if any of the following exclusion criteria apply:

1. Persisting toxicity related to prior therapy (CTCAE Grade > 1); however alopecia,sensory neuropathy Grade ≤ 2, or other Grade ≤2 AEs not constituting a safety riskbased on investigator's judgment are acceptable.

2. Prior treatment with a MEK inhibitor

3. Known history of testing positive for Human Immunodeficiency Virus (HIV) or knownacquired immunodeficiency syndrome.

4. Any significant disease that, in the opinion of the investigator, may impair thepatient's tolerance of study treatment.

5. Patients who are receiving any other investigational agents within 28 days beforestart of study treatment.

6. Prior organ transplantation including allogenic stem-cell transplantation.

7. Patients with known central nervous system metastases.

8. Active uncontrolled infection, requiring systemic therapy.

9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 monthsprior to enrollment), unstable angina, congestive heart failure (≥ New York HeartAssociation Classification Class II), or serious cardiac arrhythmia requiringmedication.

10. Severe left ventricular dysfunction as defined by ejection fraction < 45%

11. Other severe acute or chronic medical conditions including colitis, inflammatorybowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions includingrecent (within the past year) or active suicidal ideation or behaviour; orlaboratory abnormalities that may increase the risk associated with studyparticipation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this study.

12. Known maculopathy of the eye

13. Known history or current evidence of retinal vein occlusion (RVO) or current riskfactors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history ofhyperviscosity or hypercoagulability syndromes)

14. Screening corrected QT interval by Fridericia (QTcF) > 500 msec

15. Pregnant women and breastfeeding mothers are excluded due to unknown impact onembryos or infants

16. Known prior severe hypersensitivity to investigational products or any component inits formulation.

17. Concurrent use of medicines known to induce retinal toxicity (e.g. tamoxifen) or QTinterval prolonging agents.

18. Known congenital or documented acquired QT prolongation.

19. Uncorrected hypokalemia and/or hypomagnesemia.