This protocol is designed to determine the safety, tolerability, and efficacy of SGI-110 in combination with irinotecan in previously treated patients with metastatic colorectal cancer who progressed on irinotecan.
ID
Source
Brief title
Condition
- Other condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Health condition
Gemetastaseerd colorectaal carcinoom
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
During phase I, we will be assessing the safety and tolerability of SGI-110 in
combination with irinotecan, as well as determine the dose of SGI-110 that will
be used in combination with irinotecan during the phase II portion of this
trial.
Phase II: To improve median progression-free survival from that reported with
regorafenib and TAS-102 to 4 months for SGI-110+irinotecan in previously
treated metastatic colon cancer patients who have progressed on irinotecan.
Secondary outcome
In Fase I we will also be assessing the changes in global methylation and
expression at the tumor level with SGI-110 and irinotecan treatment and the
pharmacokinetic interactions of SGI-110 and irinotecan.
In phase II we will also evaluate the following: response rate as determined by
RECIST criteria 1.1, evaluate concurrent SGI-110 and irinotecan treatment
versus regorafenib alone, assess whether SGI-110 in combination with irinotecan
can improve median overall survival from the historical rate of 6.4 months, and
assess for potential predictive biomarkers of response and survival using
baseline tissue.
Background summary
Metastatic colorectal cancer (mCRC) is the second leading cause of cancer
death. The five-year survival for all patients with metastatic disease from CRC
is only 8.1%. Median survival with current generation of chemotherapies,
including oxaliplatin or irinotecan as well as newer biologic therapies such as
bevacizumab and cetuximab is only 20-24 months. Patients with mCRC have a 60%
likelihood of responding to first-line chemotherapy and drops to 10% in the
second line.
In CRC, as there are no subsequent therapy options for patients after 2nd or
3rd line therapy (based on KRAS mutational status), our group has been
exploring the potential of DNMT inhibitor therapy to synergize to subsequent
therapy. Ishiguro et al. first demonstrated that treatment with DAC resulted
in gene re-expression of known tumor suppressor genes in CRC; moreover, in both
in vitro and in vivo models, DAC treatment substantially decreased tumor growth
when combined with irinotecan or SN-38 (active irinotecan metabolite) compared
to either agent alone. In xenograft studies SGI-110 demonstrates promising
preclinical activity in both hematologic and solid tumors.
Based on these data, we hypothesize that DNMTi therapy with SGI-110 will
sensitize advanced colorectal cancer to treatment with Irinotecan.
Study objective
This protocol is designed to determine the safety, tolerability, and efficacy
of SGI-110 in combination with irinotecan in previously treated patients with
metastatic colorectal cancer who progressed on irinotecan.
Study design
This is a phase I/randomized phase II, open label, multi-institutional study
that will be conducted in two parts. First, patients will be enrolled in a
phase I study of SGI-110 combined with irinotecan in a standard 3+3 design.
After the maximum tolerated dose (MTD) is determined, patients will
subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and
irinotecan versus regorafenib or TAS-102.
Intervention
In phase I, patients will be tretated with SGI-110 (sc injection day 1-5) and
irinotecan (125 mg/m2 IV) at day (10), 8 and 15 according to the dose
escalation schedule in table 2, page 15 of the protocol.
In phase II patients in treatment arm A are treated with investigational
medicine SGI-110 (sc injection day 1-5, dose determined in phase I) combined
with irinotecan (125 mg/m2 IV day (1), 8 en 15). Patients in treatment arm B
are treated with regorafenib (tablet 160 mg/dag, day 1-21) or TAS-102 35 mg/m2
day 1-5 and 8-12.
Study burden and risks
Besides standard patient care, additional blood sampling will be done and
includes two study tumor biopsies in phase I and for a part of patients in
Phase II. Side effects of systemic therapy can occur and patients can
experience side effects or complications of the blood sampling and tumor
biopsies. The risks of participating in the study are limited, and if
successful, study treatment may benefit the subject as well. The information
that we learn from this study has the potential to improve therapy for patients
with refractory colorectal cancer, and may benefit individuals who are
diagnosed with this disease in the future.
Bunting-Blaustein Cancer Reserach building I, Orleans Street 1650
Baltimore MD 21231
NL
Bunting-Blaustein Cancer Reserach building I, Orleans Street 1650
Baltimore MD 21231
NL
Listed location countries
Age
Inclusion criteria
Histologically or cytologicaly confirmed adenocarcinoma of the colon or rectum,
Patients in phase I must have biopsiable diasese and be amenable to having two research biopsies.
Patients must have progressed on irinotecan therapy in the metastic setting. There are no limitation on number of prior therapies. They should have a life expectancy of greater than 12 weeks, an
ECOG of
Exclusion criteria
Chemotherapy or radiotherapy within 4 weeks prior to entering the study,
Known brain metastases,
Uncontrolled intercurrent illness,
Prior therapy with any hypomethylating agent,
Pregnancy
A history of a different malignancy unless disease-free for at least 5 years,
HIV positive individuals on HAART
Previoius treatement with regorafenb and TAS-102 (this applies to phase II only. If patients have previously received aeither regorafenib or tas-102, they must be able to receive the alternate regimen if randomized to the standard of care arm)
Hospitalization for an acute medical issue within 4 weeks prior to screening visit
Symptomatic bowel obstruction within 6 months prior to enrollment. Patients who undergo surgical correction of obstructing lesion will be eligible within 6 months.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-003184-62-NL |
| ClinicalTrials.gov | NCT01896856 |
| CCMO | NL45922.029.13 |