Overview
This study is designed to investigate the means by which cancer resists treatment can be overcome by a combination of an established anticancer drug, trametinib, with hydroxychloroquine.
Description
The study is a multi-centre single arm Phase 2 clinical trial to explore primary and emerging resistance mechanisms in patients with metastatic refractory pancreatic cancer treated with trametinib and hydroxychloroquine. This study will include 10-22 patients with metastatic pancreatic cancer who have previously progressed on at least one line of systemic therapy.
Eligibility
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 pancreatic
adenocarcinoma or poorly differentiated pancreatic adenocarcinoma that is amenable to
tumour biopsy.
2. Patients have received at least one line of systemic therapy for metastatic disease
and 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:
1. Serum creatinine ≤ 1.5 x ULN.
2. 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 subjects
with 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 informed
consent document.
8. Women of child-bearing potential or sexually active males must agree to use highly
effective contraceptive measures. This applies from starting treatment until at least
16 weeks after the last study drug administration. The investigator or a designated
associate is required to advise the patient how to achieve an adequate birth control.
Highly effective contraception is defined in the study as methods that achieve a
failure rate of less than 1% per year when used consistently and correctly. 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 risk
based 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 known
acquired immunodeficiency syndrome.
4. Any significant disease that, in the opinion of the investigator, may impair the
patient's tolerance of study treatment.
5. Patients who are receiving any other investigational agents within 28 days before
start 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 vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication.
10. Severe left ventricular dysfunction as defined by ejection fraction < 45%
11. Other severe acute or chronic medical conditions including colitis, inflammatory bowel
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
(within the past year) or active suicidal ideation or behaviour; or laboratory
abnormalities that may increase the risk associated with study participation or study
treatment administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the 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 risk
factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of
hyperviscosity 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 on embryos
or infants
16. Known prior severe hypersensitivity to investigational products or any component in
its formulation.
17. Concurrent use of medicines known to induce retinal toxicity (e.g. tamoxifen) or QT
interval prolonging agents.
18. Known congenital or documented acquired QT prolongation.
19. Uncorrected hypokalemia and/or hypomagnesemia.