Previously Treated Metastatic Colorectal Cancer
Conditions
Keywords
SGI-110, irinotecan, regorafenib, methylation, colorectal, metastatic, TAS-102, lonsurf
Brief summary
This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. 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 the standard of care regorafenib or Lonsurf (TAS-102).
Interventions
DRUGSGI-110 Dose Escalation
* Dose level 1 (DL1): 45 mg/m\^2 administered as a subcutaneous injection * Dose level 1G (DL1G): 45 mg/m\^2 administered as a subcutaneous injection + growth factor support * Dose level -1 (DL-1): 30 mg/m\^2 administered as a subcutaneous injection * Dose level -1G (DL-1G): 30 mg/m\^2 administered as a subcutaneous injection + growth factor support
DRUGRegorafenib
160 mg taken orally
DRUGTAS-102
35 mg/m\^2 taken orally
DRUGSGI-110
45 mg/m\^2 administered as a subcutaneous injection
DRUGIrinotecan
125 mg/m\^2 administered IV
Sponsors
Van Andel Research Institute
Astex Pharmaceuticals, Inc.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
In Phase 2, Arm B patients who have disease progression will be given the option to receive Arm A study drugs.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the colon or rectum * Phase I only: patients with biopsiable disease amenable to having two research biopsies. * Have measurable disease * Phase II only: progressed while receiving irinotecan therapy in the metastatic setting. There are no limitations on number of prior therapies in the metastatic setting. * Life expectancy of greater than 12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status \<1 * Normal organ and marrow function as defined by study-specified laboratory tests * Must use adequate contraception through the study and for 3 months after last dose of study drug.
Exclusion criteria
* Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of first dose of study drug or who have not recovered from treatment-related adverse events * Receiving any other investigational agents * Participants with known brain metastases * History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, decitabine or SGI-110. * Received prior therapy with any hypomethylating agents. * Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant or nursing women * History of a different malignancy are ineligible with exceptions (disease-free for at least 5 years with low risk for recurrence, cervical cancer in situ, definitively treated early stage prostate cancer, definitively treated breast ductal or lobular carcinoma in situ, and basal cell or squamous cell carcinoma of the skin). * HIV-positive individuals on combination antiretroviral therapy * Phase II only: previous treatment with regorafenib and TAS-102. If patients have previously received either regorafenib OR TAS-102, they must be able to receive the alternate regimen if randomized to standard of care (Arm B). * 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 outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Dose Limiting Toxicity | 28 days | Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: 1. grade 4 thrombocytopenia lasting \>7days 2. any grade 3-4 febrile neutropenia 3. grade 3 or higher non-hematologic toxicity unless it could be managed by supportive treatment 4. any other clinically significant adverse event which would place subjects at undue safety risk, or results in discontinuation of treatment. |
| Progression Free Survival (PFS) | Up to 12 months | Progression Free Survival is the time (in months) from start of treatment to progression, clinical deterioration attributed to disease, or death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 3 years | Overall Survival is defined as the time (in months) between the start of treatment and death. |
| Objective Response Rate | Assessed until disease progression, up to 3 years | Objective Response Rate (ORR) is defined as the number of subjects achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. CR = disappearance of all target lesions, PR = at least 30% decrease in the sum of diameters of target lesions. |
Countries
Netherlands, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Dose Level 1 Guadecitabine (SGI-110) 45 mg/m\^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m\^2 was administered IV on days 8 and 15 of each 28-day cycle. | 6 |
| Phase 1: Dose Level -1 Guadecitabine (SGI-110) 30 mg/m\^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m\^2 was administered IV on days 8 and 15 of each 28-day cycle. | 3 |
| Phase 1: Dose Level -1G Guadecitabine (SGI-110) 30 mg/m\^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m\^2 was administered IV on days 8 and 15 of each 28-day cycle.
Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond. | 7 |
| Phase 1: Dose Level 1G Guadecitabine (SGI-110) 45 mg/m\^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m\^2 was administered IV on days 8 and 15 of each 28-day cycle.
Growth factor support (filgrastim and peg-filgrastim) mandatory during cycle 1, and given per clinician judgement cycle 2 and beyond. | 6 |
| Phase 2: Arm A SGI-110 + Irinotecan SGI-110 45 mg/m\^2 was administered as a subcutaneous injection on days 1-5 of each 28-day cycle. Irinotecan 125 mg/m\^2 was administered IV on days 8 and 15 of each 28-day cycle. Growth factor support (filgrastim and peg-filgrastim) was given during cycle 1 with option to give additional growth factor support at subsequent cycles per clinician judgement. | 62 |
| Phase 2: Arm B Regorafenib or TAS-102 Subjects received either regorafenib or TAS-102. Regorafenib 160 mg was taken orally daily from days 1-21 of each 28-day cycle or TAS-102 35 mg/m\^2 was taken orally twice daily on days 1-5 and 8-12 of each 28-day cycle.
Subjects that had previously received one of these standard of care drugs (regorafenib or TAS-102) received the other on study. For subjects that had never received either regorafenib or TAS-102, the choice of therapy was deferred to the treating physician and patient. | 34 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Transportation issues / Non-compliance | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1: Dose Level 1 | Phase 1: Dose Level -1 | Phase 1: Dose Level -1G | Phase 1: Dose Level 1G | Phase 2: Arm A SGI-110 + Irinotecan | Phase 2: Arm B Regorafenib or TAS-102 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 54.5 years | 64 years | 52 years | 54.5 years | 55.0 years | 59.5 years | 57.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 3 Participants | 7 Participants | 6 Participants | 57 Participants | 33 Participants | 112 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 9 Participants | 4 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 3 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 6 Participants | 3 Participants | 2 Participants | 5 Participants | 47 Participants | 22 Participants | 85 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 4 Participants | 21 Participants | 18 Participants | 49 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants | 2 Participants | 41 Participants | 16 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 7 | 1 / 6 | 3 / 62 | 0 / 18 | 4 / 34 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 6 / 7 | 6 / 6 | 58 / 62 | 18 / 18 | 30 / 34 |
| serious Total, serious adverse events | 1 / 6 | 1 / 3 | 2 / 7 | 1 / 6 | 15 / 62 | 8 / 18 | 1 / 34 |
Outcome results
Primary
Number of Participants Experiencing a Dose Limiting Toxicity
Number of participants experiencing a Dose Limiting Toxicity (DLT) in each dose level. DLT is defined as any of the following study drug-related toxicities occurring during the first cycle of study drug on study: 1. grade 4 thrombocytopenia lasting \>7days 2. any grade 3-4 febrile neutropenia 3. grade 3 or higher non-hematologic toxicity unless it could be managed by supportive treatment 4. any other clinically significant adverse event which would place subjects at undue safety risk, or results in discontinuation of treatment.
Time frame: 28 days
Population: Per protocol, Dose Limiting Toxicities were only assessed in Phase 1 subjects in order to determine the Phase 2 dose of SGI-110. 1 Patient in Dose Level -1G was taken off study for non-compliance due to transportation issues before completion of Cycle 1 and was not considered evaluable for DLT analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Participants Experiencing a Dose Limiting Toxicity | 1 Participants |
| Dose Level -1 | Number of Participants Experiencing a Dose Limiting Toxicity | 2 Participants |
| Dose Level -1G | Number of Participants Experiencing a Dose Limiting Toxicity | 1 Participants |
| Dose Level 1G | Number of Participants Experiencing a Dose Limiting Toxicity | 1 Participants |
Primary
Progression Free Survival (PFS)
Progression Free Survival is the time (in months) from start of treatment to progression, clinical deterioration attributed to disease, or death.
Time frame: Up to 12 months
Population: Per protocol, the progression-free survival objective was only assessed in Phase 2 subjects. 18 subjects who received Arm B treatment were eligible to crossover to receive Arm A treatment. These participants were not included in the number analyzed in Arm A because they were not assessed for progression free survival after Arm A treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Progression Free Survival (PFS) | 2.37 months |
| Dose Level -1 | Progression Free Survival (PFS) | 2.09 months |
Secondary
Objective Response Rate
Objective Response Rate (ORR) is defined as the number of subjects achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. CR = disappearance of all target lesions, PR = at least 30% decrease in the sum of diameters of target lesions.
Time frame: Assessed until disease progression, up to 3 years
Population: ORR only assessed for Phase 2. 5 from Arm A and 2 from Arm B were excluded from response rate analysis as they didn't get a follow-up scan. 18 subjects in Arm B were eligible to crossover to receive Arm A treatment. They were not included in the number analyzed in Arm A because they were not assessed for objective response after Arm A treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Objective Response Rate | 1 Participants |
| Dose Level -1 | Objective Response Rate | 0 Participants |
Secondary
Overall Survival
Overall Survival is defined as the time (in months) between the start of treatment and death.
Time frame: Up to 3 years
Population: Per protocol, the overall survival objective was only assessed in Phase 2 subjects. 18 subjects who received Arm B treatment and were eligible to crossover to receive Arm A treatment were not included in the number analyzed in Arm A because they were not assessed for overall survival after receiving Arm A treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Level 1 | Overall Survival | 7.15 months |
| Dose Level -1 | Overall Survival | 7.66 months |