Sarcoma
Conditions
Keywords
advanced, metastatic, unresectable, soft, tissue, sarcomas
Brief summary
This is a Phase Ib/II experimental, open-label, dose escalation, active treatment study designed to determine the safety, tolerability, and recommended dose of the combination. During the Phase 2 portion of the study, we will assess progression-free survival (PFS), overall survival (OS),overall response rate (ORR), correlative endpoints, DNA methylation measured by microarray, and expression level of the genes as measured by microarray
Detailed description
Phase 1b * To determine the dose of vorinostat that can be safely combined with gemcitabine and docetaxel in patients with advanced sarcomas. * To characterize the Pharmacokinetics (PK) and Pharmacodynamics (PD) of vorinostat when combined with gemcitabine and docetaxel in patients with advanced sarcomas (Exploratory Aim). Phase 2 * To determine the safety and efficacy of gemcitabine and docetaxel in combination with vorinostat in patients with advanced sarcomas. The hypothesis is that gemcitabine and docetaxel + vorinostat will be safe and will improve the 6-months progression-free rates (PFR) of the combination by 20% (from 20% to 40%). * To determine the objective response rate, progression-free, and overall survival of patients with advanced sarcomas treated with gemcitabine and docetaxel + vorinostat; * To develop a predictive molecular signature of response to treatment in advanced sarcomas.
Interventions
DRUGDocetaxel
75 mg/m2 IV given over 60 minutes on day 8 every 21 days (1 cycle)
DRUGGemcitabine
given on days 1 and 8 at 900 mg/m2 IV over 90 minutes (fixed dose infusion rate at 10 mg/m2/min) every 21 days (1 cycle). For dose level -2, given over 67.5 minutes at 10 mg/m2/min
DRUGVorinostat
given orally at the specified dose levels (either 300 mg/daily or 200 mg twice per day) on days -1 to +2 and days +7-9 every 21 days (treatment for 3 days starting one day prior to chemotherapy on every cycle)
DRUGPegfilgrastim
administered on day 9 subcutaneously at 6 mg
Sponsors
Merck Sharp & Dohme LLC
Melissa Burgess, MD
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed soft tissue sarcoma with evidence of metastatic or unresectable disease. * Patients must have measurable disease by RECIST 1.1. * Up to 32 prior cytotoxic chemotherapy regimens in the metastatic setting are allowed. Adjuvant chemotherapy or targeted therapy will not be considered a prior line of treatment. * Age ≥18 years. * ECOG performance status ≤2 (Karnofsky ≥60%). * Life expectancy of greater than 12 weeks. * Patients must have normal organ and marrow function as defined below: * leukocytes ≥3,000/µL * absolute neutrophil count ≥1,500/µL * platelets ≥100,000/µL * total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of normal (ULN) * creatinine ≤1.5 X institutional upper limit of normal (ULN) * Peripheral neuropathy, if present, should be ≤grade 1. * Women of Child bearing potential MUST use contraceptives. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* The following specific histologic subtypes of soft tissue sarcomas will be excluded: GIST, Kaposi's sarcoma, mesothelioma, dermatofibrosarcoma, chordoma, alveolar soft-part sarcoma. Also, all bone sarcomas are excluded including Ewing's sarcoma, osteosarcoma, GIST, low grade chondrosarcoma, and chordoma. * Patients who have had treatment with chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. * Patients who are receiving any other investigational agents. * Patients with known brain metastases. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to gemcitabine, docetaxel, vorinostat, or G-CSF. * Patients who have received and progressed on the combination of gemcitabine and docetaxel in the metastatic setting. * 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 and breastfeeding women * Patients taking concomitant HDAC inhibitors. * HIV-positive patients on combination antiretroviral treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Recommended Phase II Dose of Vorinostat | During Cycle 1 of treatment | Recommended Phase ll dose of vorinostat that can be safely combined with gemcitabine and docetaxel. Gemcitabine and docetaxel were given at a fixed dose while vorinostat was dose-escalated using a standard '3+3' design. Dose-limiting toxicity (DLT) is defined as specific study drug-related events experienced during Cycle 1; only DLTs observed in a patient during the first cycle of treatment will be used for the dose escalation decision. |
| Six-month Progression-free Survival (PFS) | Up to 6 months (per patient) | Proportion of participants whose disease does not progress within 6 months of start of treatment (number of patients without progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| One-year Progression-free Survival (PFS) | Up to one year (per patient) | Proportion of participants whose disease does not progress within one year of start of treatment (number of patients with progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression. |
| Overall Survival (OS) | Up to 7 years and 7 months | The median length of time from the start of treatment that diagnosed study participants remain alive. |
| Objective Response Rate (ORR) | Up to 7 years and 7 months | Number of patients with Complete response \[CR\] + partial response \[PR\], per RECIST v1.1 criteria . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to \<10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters |
| One-year Overall Survival (OS) | Up to one year (per patient) | Proportion of participants alive at one year from the start of treatment. |
| Six-month Overall Survival (OS) | Up to 6 months (per patient) | Proportion of participants alive at six months from the start of treatment. |
| Progression-free Survival (PFS) | Up to 7 years and 7 months | The median length of time from the beginning of study treatment that patients remain alive without progression of their disease (cancer). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression. |
Countries
United States
Participant flow
Pre-assignment details
Analysis of Phase 2 group includes (6) patients who enrolled to the Phase 1b group at Dose Level 1.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Dose Level 1:
Docetaxel: 75 mg/m2 IV over 60 minutes on day 8 every 21 days (1 cycle).
Gemcitabine: given on days 1 and 8 at 900 mg/m2 IV over 90 minutes (fixed dose infusion rate at 10 mg/m2/min) every 21 days (1 cycle).
Vorinostat: 300 mg daily given orally on days -1 to +2 and days +7-9 every 21 days (treatment for 3 days starting one day prior to chemotherapy on every cycle).
Pegfilgrastim: Administered on day 9 subcutaneously at 6 mg. | 31 |
| Dose Level 2 Dose Level 2:
Docetaxel: 75 mg/m2 IV over 60 minutes on day 8 every 21 days (1 cycle).
Gemcitabine: given on days 1 and 8 at 900 mg/m2 IV over 90 minutes (fixed dose infusion rate at 10 mg/m2/min) every 21 days (1 cycle).
Vorinostat: 200 mg twice daily given orally on days -1 to +2 and days +7-9 every 21 days (treatment for 3 days starting one day prior to chemotherapy on every cycle).
Pegfilgrastim: Administered on day 9 subcutaneously at 6 mg. | 6 |
| Total | 37 |
Baseline characteristics
| Characteristic | Dose Level 2 | Total | Dose Level 1 |
|---|---|---|---|
| Age, Continuous | 50.50 years STANDARD_DEVIATION 17.03 | 55.03 years STANDARD_DEVIATION 15.54 | 56.68 years STANDARD_DEVIATION 15.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 35 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 33 Participants | 27 Participants |
| Sex: Female, Male Female | 3 Participants | 24 Participants | 21 Participants |
| Sex: Female, Male Male | 3 Participants | 13 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 26 / 31 | 5 / 6 |
| other Total, other adverse events | 31 / 31 | 6 / 6 |
| serious Total, serious adverse events | 19 / 31 | 3 / 6 |
Outcome results
Primary
Phase I: Recommended Phase II Dose of Vorinostat
Recommended Phase ll dose of vorinostat that can be safely combined with gemcitabine and docetaxel. Gemcitabine and docetaxel were given at a fixed dose while vorinostat was dose-escalated using a standard '3+3' design. Dose-limiting toxicity (DLT) is defined as specific study drug-related events experienced during Cycle 1; only DLTs observed in a patient during the first cycle of treatment will be used for the dose escalation decision.
Time frame: During Cycle 1 of treatment
Population: Patients treated with combination therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Phase I: Recommended Phase II Dose of Vorinostat | 300 mg/day of Vorinostat |
Primary
Six-month Progression-free Survival (PFS)
Proportion of participants whose disease does not progress within 6 months of start of treatment (number of patients without progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
Time frame: Up to 6 months (per patient)
Population: Patients that received combination therapy that were evaluable for response to treatment.~Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Six-month Progression-free Survival (PFS) | 0.473 proportion of participants |
Secondary
Objective Response Rate (ORR)
Number of patients with Complete response \[CR\] + partial response \[PR\], per RECIST v1.1 criteria . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to \<10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters
Time frame: Up to 7 years and 7 months
Population: Patients that received combination therapy. Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Objective Response Rate (ORR) | 7 Participants |
Secondary
One-year Overall Survival (OS)
Proportion of participants alive at one year from the start of treatment.
Time frame: Up to one year (per patient)
Population: Patients that received combination therapy. Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | One-year Overall Survival (OS) | 0.477 proportion of participants |
Secondary
One-year Progression-free Survival (PFS)
Proportion of participants whose disease does not progress within one year of start of treatment (number of patients with progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
Time frame: Up to one year (per patient)
Population: Patients that received combination therapy that were evaluable for response to treatment.~Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | One-year Progression-free Survival (PFS) | 0.304 proportion of participants |
Secondary
Overall Survival (OS)
The median length of time from the start of treatment that diagnosed study participants remain alive.
Time frame: Up to 7 years and 7 months
Population: Patients that received combination therapy. Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Overall Survival (OS) | 11.92608 months |
Secondary
Progression-free Survival (PFS)
The median length of time from the beginning of study treatment that patients remain alive without progression of their disease (cancer). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
Time frame: Up to 7 years and 7 months
Population: Patients that received combination therapy that were evaluable for response to treatment.~Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Progression-free Survival (PFS) | 5.552361 months |
Secondary
Six-month Overall Survival (OS)
Proportion of participants alive at six months from the start of treatment.
Time frame: Up to 6 months (per patient)
Population: Patients that received combination therapy. Note: Six of the twelve patients enrolled to the Phase 1b group at Dose Level 1 / RP2D were analyzed with the Phase 2 group due to same dose level of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Docetaxel + Gemcitabine + Vorinostat + Pegfilgrastim | Six-month Overall Survival (OS) | 0.742 proportion of participants |