Overview

LY3200882 and Capecitabine in Advanced Resistant TGF-beta Activated Colorectal Cancer (EORTC1615)

Status:
Unknown status
Trial end date:
2021-07-01
Target enrollment:
0
Participant gender:
All
Summary
Part I of this study is designed to identify the recommended phase 2 dose (RP2D) of the combination regimen of LY3200882/capecitabine as second line treatment in patients with 5-FU or capecitabine resistant CRC. Part II is designed to obtain proof of principle of the LY3200882 plus capecitabine combination in patients with chemo-resistant CRC. The combination of LY3200882 plus capecitabine will be given as second line therapy in the phase II part of this study. Patients with chemotherapy resistant activated TGF-β signature-like tumors will have received a fluoropyrimidine (5FU or capecitabine) in the first line of chemotherapy, usually combined with oxaliplatin and, depending upon local hospital preferences or national guidelines, also bevacizumab, or cetuximab/panitumumab if the tumor is KRAS wild type. Addition of LY3200882 to capecitabine should thus result in reversal of unresponsiveness, which is the first step in exploring this concept in the clinic. Capecitabine can be used as single agent in advanced CRC and is thus attractive for this study concept. If proof of principle is achieved also other tumor types can be explored with this genetic makeup, such as non-small cell lung cancer (NSCLC) in second line of treatment after platinum doublet therapy in first line, usually cisplatin/carboplatin-pemetrexed in non-squamous and cisplatin/carboplatin-gemcitabine or cisplatin/carboplatin-paclitaxel in squamous type NSCLC.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
The Netherlands Cancer Institute
Collaborators:
Agendia
Azienda Ospedaliera Niguarda Cà Granda
Catalan Institute of Health
Eli Lilly and Company
European Organisation for Research and Treatment of Cancer - EORTC
Fundación para la Investigación del Hospital Clínico de Valencia
Universitaire Ziekenhuizen Leuven
University of Campania "Luigi Vanvitelli"
University of Turin, Italy
Vall d'Hebron Institute of Oncology
Treatments:
Capecitabine
Criteria
Inclusion Criteria:

1. Histological or cytological proof of CRC;

2. Disease progression or relapse upon at least one line of treatment for advanced CRC
with fluoropyrimidine containing chemotherapy as single agent or in combination
(combinations with oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab are
allowed);

3. Written documentation of activated TGF-β signature-like gene signature, as determined
by the validated assay of Agendia;

4. Age ≥ 18 years;

5. Able and willing to give written informed consent;

6. WHO performance status of ≤ 1;

7. LVEF ≥ 55%;

8. Able and willing to undergo blood sampling for PK and PD analysis;

9. Able and willing to undergo tumor biopsies before start, during treatment and at the
end of treatment

10. Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and
anti-tumor activity;

11. Evaluable disease according to RECIST 1.1 criteria (measurable disease for the phase
II part; evaluable disease is sufficient for the phase I part);

12. Minimal acceptable safety laboratory values

1. ANC of ≥ 1.5 x 109 /L

2. Platelet count of ≥ 100 x 109 /L

3. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 3.0 x
ULN, or ALAT and ASAT ≤ 5 x ULN in patients with liver metastases

4. Renal function as defined by serum creatinine ≤1.5 x ULN

5. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);

13. Negative pregnancy test (urine or serum) for female patients with childbearing
potential.

Exclusion Criteria:

1. Any treatment with investigational drugs within 30 days prior to receiving the first
dose of investigational treatment;

2. Known or suspected dihydropirimidine dehydrogenase deficit (Mutant for DPD*2A
genotype, 1236 GA genotype, 1679TG genotype and 2846A>T genotype);

3. Symptomatic or untreated leptomeningeal disease;

4. Symptomatic brain metastasis. Patients previously treated or untreated for these
conditions that are asymptomatic in the absence of corticosteroid therapy are allowed
to enrol. Brain metastasis must be stable with verification by imaging (e.g. brain MRI
or CT (<21 days before start of treatment) completed at screening demonstrating no
current evidence of progressive brain metastases). Patients are not permitted to
receive enzyme inducing anti-epileptic drugs or corticosteroids;

5. History of cardiac disease, including myocardial infarction within 6 months before
study entry, unstable angina pectoris, New York Heart Association Class III/IV
congestive heart failure, or uncontrolled hypertension, major cardiac abnormalities, a
predisposition for developing aneurysms including family history of aneurysms, Marfan
syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the
heart.

6. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LY3200882 (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection);

7. Woman who are pregnant or breast feeding;

8. Radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of
investigational treatment. Palliative radiation (1x 8Gy) is allowed;

9. Patients who have undergone any major surgery within the last 2 weeks prior to
starting study drug or who would not have fully recovered from previous surgery;

10. Active infection requiring systemic antibiotics or uncontrolled infectious disease;

11. Patients with a known history of hepatitis B or C or known Human Immunodeficiency
Virus HIV-1 or HIV-2 type patients;

12. Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or that may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for the
study;

13. Known hypersensitivity to one of the study drugs or excipients.

14. For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per
year (when used consistently and correctly) during the treatment period and for at
least 90 days after the last dose of LY3200882 and/or capecitabine. More information
is available in section 5.2.4.

15. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined in
section 5.2.4.