Pancreatic Cancer, Solid Tumors
Conditions
Brief summary
This is a study of ruxolitinib in combination with gemcitabine with or without nab-paclitaxel administered to patients with advanced or metastatic pancreatic cancer. The study will be conducted in two parts. Part 1 of the study will evaluate the safety, tolerability and pharmacokinetics (PK) of ruxolitinib when given as described to patients with advanced or metastatic pancreatic cancer. A goal of Part 1 will be to identify the maximally tolerated dose (MTD) of ruxolitinib when given with gemcitabine with or without nab-paclitaxel. This dose will be selected for use in Part 2 of the study. Part 2 of the study will further evaluate the safety, tolerability, PK and preliminary clinical activity of ruxolitinib at the dose defined in Part 1 used in combination with gemcitabine with or without nab-paclitaxel in subjects with advanced or metastatic pancreatic cancer. After multiple challenges of trial conduct, by mutual agreement between investigators and sponsor, dose escalation ended after Cohort B1, RUX 10 mg twice daily (BID) - GCSF in October 2014. Therefore, the MTD was not reached. No safety issues led to the decision to stop further enrollment. Because of the early study termination, samples for pharmacokinetics and pharmacodynamics, and computed tomography for tumor burden were collected, but not analyzed; analysis data are not available. The data cutoff for this posting is 22 SEP 2015. As of the data cutoff, 1 subject was receiving treatment in the study and had been enrolled for 47 weeks. This subject had their end of treatment visit in AUG 2016. A comparison of this subjects' safety data after the cutoff date showed no clinically meaningful differences (eg, adverse events) compared with safety results that are summarized here.
Interventions
DRUGruxolitinib
DRUGgemcitabine
Other names: Gemzar®
DRUGnab-paclitaxel
Other names: Abraxane®
DRUGfilgrastim
Prophylactic GCSF support was filgrastim and was given in Cycle 1 on Days 2 to 5, 9 to 12, and 16 to 19, unless chemotherapy was held for toxicity, then prophylactic GCSF support was also held.
Sponsors
Incyte Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 18 years or older * Histologically or cytologically confirmed adenocarcinoma of the pancreas * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 * Requirements for prior therapy as outlined below: * Enrollment into Regimen A: received no more than 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy) * Enrollment into Regimen B: received no prior chemotherapy for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy) * Adequate renal, hepatic, and bone marrow function without blood product or hematopoietic growth factor support: * Able to swallow and retain oral medication
Exclusion criteria
* Any known contraindications to the use of gemcitabine (for enrollment in Regimen A or B) or nab-paclitaxel (for enrollment into Regimen B). * Evidence of uncontrolled brain metastases or history of uncontrolled seizures. * Ongoing radiation therapy and/or radiation therapy administered within 28 days of enrollment. Subjects who have received radiation to the spine, pelvis, ribs, or femur should be discussed with the sponsor, as extensive radiation to marrow forming region may compromise a subject's ability to tolerate myelosuppressive chemotherapy. Subjects who have ongoing radiotherapy-related toxicities are not eligible. * Subjects who participated in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) prior to first dose. * Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or other noninvasive malignancy without sponsor approval. * Inability to swallow food or any condition of the upper GI tract that precludes administration of oral medications. * Recent (≤ 3 months) history of partial or complete bowel obstruction. * Unwilling to be transfused with blood components. * Known history of Hepatitis B or C infection or HIV infection. * Presence of ≥ Grade 2 neuropathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | Approximately 28 days | Toxicities occurring during the first treatment cycle (Cycle 1) defined tolerability. Within each cohort, subjects were considered evaluable if they had received at least 40 of 56 planned doses of RUX during the 28-day surveillance period and received 2 of the 3 planned doses of chemotherapy (gemcitabine and/or gemcitabine and nab-paclitaxel) at the assigned dose level, or they had experienced a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations Will be Used to Estimate Peak Plasma Concentration (Cmax) and Area Under the Plasma Concentration Curve (AUC). | Day 1 and Day 8 | — |
| Plasma Concentration of Tumor Specific Biomarkers and Cytokines Before and During Treatment. | Up to 6 months | — |
| Clinical Activity as Measured by the Greatest Decrease in Tumor Burden Compared to Baseline. | Approximately 6 months | — |
| Percentage of Responders | Randomization to clinical cutoff 22Sept2015 (approx 244 days) | Duration of response was measured as the time from the first overall response contributing to an objective response to the first overall response of progressive disease (PD) occurring after the first overall response contributing to the objective response. |
| Duration of Response | Randomization to clinical cutoff 22Sept2015 (approx 244 days) | Duration of response was the time from the first overall response contributing to an objective response to the first overall response of progressive disease (PD) occurring after the first overall response contributing to the objective response. Confidence intervals for median duration of response were calculated using the method of Brookmeyer and Crowley (1982). |
| Percentage of Participants With a Best Response by RECIST Criteria | every 2 cycles starting at Cycle 3 Day 1 up to approximately 4 to 6 months | Best response was determined on the subject level using the highest overall response achieved post-baseline. In the case of stable disease (SD), measurements had to meet the SD criterion at least once after study entry at a minimum interval of 49 days. Subjects who failed to meet this criterion had best response of progressive disease (PD) if the next available RECIST evaluation after the initial scan indicated PD or not evaluable (NE) if no additional RECIST evaluations were available. Complete Response (CR) and Partial Response (PR) defined by the Response Evaluation Criteria in Solid Tumor (RECIST) criteria. CR: Disappearance of all target and nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, or persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort A0 RUX 15 mg BID; Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 | 16 |
| Cohort B (-1) RUX Orally, Twice Daily 5 mg BID; Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15; nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15; + GCSF | 4 |
| Cohort B0 (+GCSF) RUX 10 mg BID; Gemcitabine 1000 mg/m\^2; nab-Paclitaxel 100 mg/m\^2; +GCSF | 10 |
| Cohort B0 (-GCSF) RUX 10 mg BID; Gemcitabine 1000 mg/m\^2; nab-Paclitaxel 100 mg/m\^2; -GCSF | 4 |
| Cohort B1 RUX 10 mg BID; Gemcitabine 1000 mg/m\^2; nab-Paclitaxel 100 mg/m\^2; - GCSF given in Cycle 1 on Days 2 to 5, 9 to 12, and 16 to 19 | 8 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Death | 2 | 2 | 1 | 0 | 0 |
| Overall Study | Disease progression | 11 | 1 | 7 | 2 | 6 |
| Overall Study | disease progression & patient preference | 2 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A0 | Cohort B (-1) | Cohort B0 (+GCSF) | Cohort B0 (-GCSF) | Cohort B1 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 8.56 | 61.3 years STANDARD_DEVIATION 6.4 | 61.2 years STANDARD_DEVIATION 9.33 | 70.0 years STANDARD_DEVIATION 7.62 | 62.4 years STANDARD_DEVIATION 8.48 | 62.8 years STANDARD_DEVIATION 8.45 |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 6 participants | 2 participants | 8 participants | 3 participants | 5 participants | 24 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 10 participants | 2 participants | 2 participants | 1 participants | 3 participants | 18 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 2 | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 6 Participants | 0 Participants | 2 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 0 Participants | 4 Participants | 4 Participants | 6 Participants | 22 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 16 | 4 / 4 | 10 / 10 | 4 / 4 | 8 / 8 |
| serious Total, serious adverse events | 10 / 16 | 4 / 4 | 3 / 10 | 0 / 4 | 2 / 8 |
Outcome results
Primary
Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs)
Toxicities occurring during the first treatment cycle (Cycle 1) defined tolerability. Within each cohort, subjects were considered evaluable if they had received at least 40 of 56 planned doses of RUX during the 28-day surveillance period and received 2 of the 3 planned doses of chemotherapy (gemcitabine and/or gemcitabine and nab-paclitaxel) at the assigned dose level, or they had experienced a DLT.
Time frame: Approximately 28 days
Population: Safety population included all enrolled subjects who received at least 1 dose of RUX.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A0 | Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | 0.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | 0.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | 20.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | 50.0 percentage of participants |
| Cohort B1 | Percentage of Participants With Adverse Events That Are Defined as Dose Limiting Toxicities (DLTs) | 0.0 percentage of participants |
Secondary
Clinical Activity as Measured by the Greatest Decrease in Tumor Burden Compared to Baseline.
Time frame: Approximately 6 months
Population: Enrollment of additional study cohorts was stopped after Cohort B1, RUX 10 mg BID-GCSF; Part 2 of the study was not conducted. Because of the early study termination, samples for pharmacokinetics and pharmacodynamics, and computed tomography for tumor burden were collected, but not analyzed; analysis data are not available.
Secondary
Duration of Response
Duration of response was the time from the first overall response contributing to an objective response to the first overall response of progressive disease (PD) occurring after the first overall response contributing to the objective response. Confidence intervals for median duration of response were calculated using the method of Brookmeyer and Crowley (1982).
Time frame: Randomization to clinical cutoff 22Sept2015 (approx 244 days)
Population: Intent-to-Treat Population (ITT) population - All subjects who received at least 1 dose of RUX
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A0 | Duration of Response | 132.0 days |
| Cohort B (-1) | Duration of Response | 33.0 days |
| Cohort B0 (+GCSF) | Duration of Response | 113.0 days |
| Cohort B0 (-GCSF) | Duration of Response | 244.0 days |
| Cohort B1 | Duration of Response | 225.0 days |
Secondary
Percentage of Participants With a Best Response by RECIST Criteria
Best response was determined on the subject level using the highest overall response achieved post-baseline. In the case of stable disease (SD), measurements had to meet the SD criterion at least once after study entry at a minimum interval of 49 days. Subjects who failed to meet this criterion had best response of progressive disease (PD) if the next available RECIST evaluation after the initial scan indicated PD or not evaluable (NE) if no additional RECIST evaluations were available. Complete Response (CR) and Partial Response (PR) defined by the Response Evaluation Criteria in Solid Tumor (RECIST) criteria. CR: Disappearance of all target and nontarget lesions. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, or persistence of 1 or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits.
Time frame: every 2 cycles starting at Cycle 3 Day 1 up to approximately 4 to 6 months
Population: Intent-to-Treat (ITT) Population - All subjects who received at least 1 dose of RUX
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Overall response | 12.5 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Missing | 18.8 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Not evaluable | 6.3 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Partial response | 12.5 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Complete response | 0.0 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Stable disease | 25.0 percentage of participants |
| Cohort A0 | Percentage of Participants With a Best Response by RECIST Criteria | Progressive disease | 37.5 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Progressive disease | 0.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Stable disease | 75.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Complete response | 0.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Overall response | 25.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Not evaluable | 0.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Partial response | 25.0 percentage of participants |
| Cohort B (-1) | Percentage of Participants With a Best Response by RECIST Criteria | Missing | 0.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Stable disease | 20.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Overall response | 50.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Complete response | 0.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Partial response | 50.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Progressive disease | 10.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Not evaluable | 0.0 percentage of participants |
| Cohort B0 (+GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Missing | 20.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Partial response | 0.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Progressive disease | 0.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Complete response | 25.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Missing | 25.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Not evaluable | 0.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Overall response | 25.0 percentage of participants |
| Cohort B0 (-GCSF) | Percentage of Participants With a Best Response by RECIST Criteria | Stable disease | 50.0 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Partial response | 37.5 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Missing | 0.0 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Not evaluable | 0.0 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Progressive disease | 37.5 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Complete response | 0.0 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Overall response | 37.5 percentage of participants |
| Cohort B1 | Percentage of Participants With a Best Response by RECIST Criteria | Stable disease | 25.0 percentage of participants |
Secondary
Percentage of Responders
Duration of response was measured as the time from the first overall response contributing to an objective response to the first overall response of progressive disease (PD) occurring after the first overall response contributing to the objective response.
Time frame: Randomization to clinical cutoff 22Sept2015 (approx 244 days)
Population: Intent-to-Treat Population (ITT) population - All subjects who received at least 1 dose of RUX
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A0 | Percentage of Responders | 12.5 Percentage of responders |
| Cohort B (-1) | Percentage of Responders | 25.0 Percentage of responders |
| Cohort B0 (+GCSF) | Percentage of Responders | 50.0 Percentage of responders |
| Cohort B0 (-GCSF) | Percentage of Responders | 25.0 Percentage of responders |
| Cohort B1 | Percentage of Responders | 37.5 Percentage of responders |
Secondary
Plasma Concentration of Tumor Specific Biomarkers and Cytokines Before and During Treatment.
Time frame: Up to 6 months
Population: Enrollment of additional study cohorts was stopped after Cohort B1, RUX 10 mg BID-GCSF; Part 2 of the study was not conducted.Because of the early study termination, samples for pharmacokinetics and pharmacodynamics, and computed tomography for tumor burden were collected, but not analyzed; analysis data are not available.
Secondary
Plasma Concentrations Will be Used to Estimate Peak Plasma Concentration (Cmax) and Area Under the Plasma Concentration Curve (AUC).
Time frame: Day 1 and Day 8
Population: Further enrollment of additional study cohorts was stopped after Cohort B1, RUX 10 mg BID - GCSF; Part 2 of the study was not conducted. Because of the early study termination, samples for pharmacokinetics and pharmacodynamics, and computed tomography for tumor burden were collected, but not analyzed; analysis data are not available.