Adenocarcinoma of the Pancreas
Conditions
Brief summary
The investigators' long-term goal is to improve the survival of patients with pancreatic cancer by enhancing the efficacy of gemcitabine-radiation by adding the Wee1 inhibitor MK-1775.
Interventions
DRUGMK-1775
MK-1775 will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .
DRUGGemcitabine
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.
RADIATIONRadiation Therapy
52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy.
Sponsors
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have pathologically confirmed adenocarcinoma of the pancreas. * Patients will have unresectable disease, defined radiographically as \>180 degrees involvement of the superior mesenteric artery or celiac trunk or SMV/portal vein impingement that cannot be surgically reconstructed, in the absence of distant metastasis.. * Patients must have a Zubrod performance status (measure of general well being that ranges from 0 to 5 where 0 represents perfect health) of \< 2. * Patients must have adequate organ function defined as follows: absolute neutrophil count of ≥ 1500/mm3, platelets ≥ 100,000/mm3, serum creatinine ≤ 2 mg/dl, total bilirubin ≤ 3, (with relief of biliary obstruction if present (PTC tube or endobiliary stent)) and AST \< 5 times the upper limit of normal. * Patients of reproductive potential must agree to use an effective contraceptive method during participation in this trial and for 6 months after the trial. Patients must not be breastfeeding. * Patients must be aware of the investigational nature of the therapy and provide written informed consent. * Patients must be at least 18 years old.
Exclusion criteria
* Other serious uncontrolled concomitant systemic disorders or psychiatric condition that would interfere with the safe delivery of protocol therapy. * A history of previous chemotherapy for pancreatic cancer or abdominal radiation therapy. * The use of any investigational agent in the month before enrollment into the study. * Inability to discontinue a prescription or non-prescription drugs or other products known to be metabolized by CYP3A4, or to inhibit or induce CYP3A4 prior to Day 1 of dosing and to withhold throughout the study until 2 weeks after the last dose of study medication. Medications of particular concern are the following inhibitors of CYP3A4: azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, aprepitant, HIV protease inhibitors, nefazodone and the following inducers of CYP3A4: phenytoin, barbiturates and rifampicin. Substrates of CYP3A4 include statins (lovastatin, simvastatin), midazolam, terfenadine, astemizole, and cisapride.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of AZD1775 (MK-1775) When Used Concurrently With Gemcitabine and Radiation Therapy. | The observation period for MTD is defined as the first 4 cycles of treatment (with a 3 week break between cycle 3 and cycle 4), for a total of 105 days in length. | Probability of dose limiting toxicities was calculated for each dose (p\[DLT/d\]) using the Time to Event Continual Reassessment Method (TITE-CRM). The target DLT rate was 0.30. Dose level 1 (150 mg AZD1775) was determined to be the MTD and recommended phase 2 dose (RP2D). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Phosphorylation Inhibition of Greater Than 0 | First cycle of treatment | During the first cycle of treatment, patients underwent 2 biopsies: 3 h after treatment with gemcitabine (but before MK- 1775), and 2 hours after MK-1775. WEE1 signaling was assessed using immunohistochemistry (IHC) to measure phosphorylation of various markers including Cdk1 (Y15). Inhibition was quantified as the within subject change in the above markers between the two biopsy timepoints. Descriptive statistics of inhibition across subjects (for each marker) were calculated and reported by dose level. |
| Overall Survival | Up to 48 months following treatment | Overall survival (OS) summarized by Kaplan-Meier curves and characterized by descriptive statistics such as median OS. The time frame for data collection for OS varied depending on the length of patient follow-up, which ranged from 1.8 months to 47.2 months. Patients who enrolled soon after the study opened may have been followed longer than patients who enrolled later, toward the end of the study. |
| Time From Date of Registration to Date of Documented Disease Progression | Up to 48 months following treatment | Time from date of registration to date of documented disease progression summarized by Kaplan-Meier method. The time frame for data collection varied depending on the length of patient follow-up, which ranged from 1.8 months to 47.2 months. Patients who enrolled soon after the study opened may have been followed longer than patients who enrolled later, toward the end of the study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AZD-1775 100 mg AZD-1775 (MK-1775) 100 mg will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.
Radiation Therapy: 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy. only in cycles 2 and 3 | 1 |
| AZD-1775 125 mg AZD-1775 (MK-1775) 125 mg will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.
Radiation Therapy: 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy. only in cycles 2 and 3 | 13 |
| AZD-1775 150 mg AZD-1775 (MK-1775) 150 mg will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.
Radiation Therapy: 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy. only in cycles 2 and 3 | 9 |
| AZD-1775 175 mg AZD-1775 (MK-1775) 175 mg will be given as an oral capsule on days 1 and 2, and on days 8 and 9 of every 3-week cycle .
Gemcitabine 1000mg/m2 will be infused over 30 minutes on days 1 and 8 of a 3 -week treatment cycle.
Radiation Therapy: 52.5Gy in 25 fractions (2.1Gy/fraction), using intensity modulated radiation therapy (IMRT). Radiation therapy will be administered after chemotherapy. only in cycles 2 and 3 | 11 |
| Total | 34 |
Baseline characteristics
| Characteristic | AZD-1775 100 mg | AZD-1775 125 mg | AZD-1775 150 mg | AZD-1775 175 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 74 years | 66 years | 62 years | 60 years | 68 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 11 Participants | 9 Participants | 10 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 13 Participants | 7 Participants | 11 Participants | 32 Participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 4 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 7 Participants | 5 Participants | 7 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 9 / 13 | 5 / 9 | 6 / 11 |
| other Total, other adverse events | 0 / 1 | 3 / 13 | 3 / 9 | 4 / 11 |
| serious Total, serious adverse events | 1 / 1 | 5 / 13 | 4 / 9 | 8 / 11 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of AZD1775 (MK-1775) When Used Concurrently With Gemcitabine and Radiation Therapy.
Probability of dose limiting toxicities was calculated for each dose (p\[DLT/d\]) using the Time to Event Continual Reassessment Method (TITE-CRM). The target DLT rate was 0.30. Dose level 1 (150 mg AZD1775) was determined to be the MTD and recommended phase 2 dose (RP2D).
Time frame: The observation period for MTD is defined as the first 4 cycles of treatment (with a 3 week break between cycle 3 and cycle 4), for a total of 105 days in length.
Population: All participants who received at least one dose of the study drug were evaluable for MTD.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1775 (MK-1775), Gemcitabine, Radiation Therapy | Maximum Tolerated Dose (MTD) of AZD1775 (MK-1775) When Used Concurrently With Gemcitabine and Radiation Therapy. | 150 mg |
Secondary
Number of Patients With Phosphorylation Inhibition of Greater Than 0
During the first cycle of treatment, patients underwent 2 biopsies: 3 h after treatment with gemcitabine (but before MK- 1775), and 2 hours after MK-1775. WEE1 signaling was assessed using immunohistochemistry (IHC) to measure phosphorylation of various markers including Cdk1 (Y15). Inhibition was quantified as the within subject change in the above markers between the two biopsy timepoints. Descriptive statistics of inhibition across subjects (for each marker) were calculated and reported by dose level.
Time frame: First cycle of treatment
Population: 20 participants were evaluable for this outcome measure. Two sequential skin punch biopsies were obtained from 20 of the 34 study participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1775 (MK-1775), Gemcitabine, Radiation Therapy | Number of Patients With Phosphorylation Inhibition of Greater Than 0 | 1 participants |
| AZD-1775 125 mg | Number of Patients With Phosphorylation Inhibition of Greater Than 0 | 7 participants |
| AZD-1775 150 mg | Number of Patients With Phosphorylation Inhibition of Greater Than 0 | 3 participants |
| AZD-1775 175 mg | Number of Patients With Phosphorylation Inhibition of Greater Than 0 | 5 participants |
Secondary
Overall Survival
Overall survival (OS) summarized by Kaplan-Meier curves and characterized by descriptive statistics such as median OS. The time frame for data collection for OS varied depending on the length of patient follow-up, which ranged from 1.8 months to 47.2 months. Patients who enrolled soon after the study opened may have been followed longer than patients who enrolled later, toward the end of the study.
Time frame: Up to 48 months following treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1775 (MK-1775), Gemcitabine, Radiation Therapy | Overall Survival | 21.96 months |
| AZD-1775 125 mg | Overall Survival | 21.73 months |
| AZD-1775 150 mg | Overall Survival | 23.84 months |
| AZD-1775 175 mg | Overall Survival | 22.45 months |
Secondary
Time From Date of Registration to Date of Documented Disease Progression
Time from date of registration to date of documented disease progression summarized by Kaplan-Meier method. The time frame for data collection varied depending on the length of patient follow-up, which ranged from 1.8 months to 47.2 months. Patients who enrolled soon after the study opened may have been followed longer than patients who enrolled later, toward the end of the study.
Time frame: Up to 48 months following treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1775 (MK-1775), Gemcitabine, Radiation Therapy | Time From Date of Registration to Date of Documented Disease Progression | 8.05 months |
| AZD-1775 125 mg | Time From Date of Registration to Date of Documented Disease Progression | 9.44 months |
| AZD-1775 150 mg | Time From Date of Registration to Date of Documented Disease Progression | 9.90 months |
| AZD-1775 175 mg | Time From Date of Registration to Date of Documented Disease Progression | 6.08 months |