Diffuse Large B Cell Non-Hodgkin Lymphoma
Conditions
Keywords
DLBCL
Brief summary
This is a single institution phase I/II study using an ADAM17 inhibitor (INCB7839) with rituximab as consolidation therapy after an autologous hematopoietic cell transplant (HCT) for patients with diffuse large B cell lymphoma (DLBCL). The study consists of two phases. The dose finding phase is a modified version of a phase I trial and the extended phase is a modified version of a phase II trial.
Detailed description
The primary goal of the dose finding phase is to determine the maximum tolerated dose (MTD) of INCB7839. Up to three dose levels will be tested (100 mg bid, 200 mg bid, and 300 mg bid). As the 300 mg bid has been proven safe in the non-transplant setting, dose escalation follows a Fast-Track Design with 1 patient enrolled per dose level unless a grade 2 or greater treatment emergent event occurs within the 1st 14 days of INCB7839. At that point, dose escalation converts to a standard 3+3 design and two additional patients are enrolled at the current dose level. If dose level 3 is completed without dose limiting toxicity (DLT) in the 1st 3 patients, an additional 3 patients will be enrolled at this level (without the staggering required by the DLT rules) prior to moving to the phase II component. Once the phase I dose escalation is completed, an additional 12 patients will be enrolled at the MTD (or dose level 3, if no DLT) to obtain a more detailed toxicity profile as well as a preliminary estimate of progression free survival at 6 months post-transplant.
Interventions
DRUGRituximab
Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later
DRUGINCB7839
INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Fast-Track Design with 1 patient enrolled per dose level until a grade 2 or greater treatment emergent adverse event occurs. A treatment emergent adverse event is any event not present prior to the initiation of the treatment (INCB7839) or any event already present that worsens in either intensity or frequency following exposure to the treatment. At that point, dose escalation will convert to a standard 3+3 design with two additional patients enrolled at the same dose level. If dose level 3 is completed without dose limiting toxicity (DLT) in the 1st 3 patients, an additional 3 patients will be enrolled at this level (without the staggering required by the DLT rules) prior to moving to the phase II component. Once the phase I dose escalation is completed, an additional 12 patients will be enrolled at the MTD (or dose level 300mg bid, if no DLT) to obtain a more detailed toxicity profile as well as a preliminary estimate of progression free survival at 6 months post-transplant.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients 18 years or older who have undergone an autologous HCT for the treatment of DLBCL and are in a complete remission (CR), partial remission (PR) or have stable disease (SD) at the day 28 post-transplant reassessment * Karnofsky Score of ≥ 70% (appendix II) * Able to start the protocol therapy (1st dose of rituximab) between day 28-75 post-transplant * Adequate organ function defined as: * Hematologic: platelets ≥ 50,000 x 109/L; ANC ≥ 1000 x 109/L unsupported by G-CSF or GM-CSF for 3 days * Renal: creatinine \< 1.5 mg/dl or glomerular filtration rate \> 50 ml/min * Hepatic: Alanine transaminase (ALT, SGPT) and aspartate aminotransferase (SGOT, AST) \< 3 x upper limit of institutional normal and total bilirubin \< 3.0 mg/dl (if total bilirubin is ≥ 3.0 patient is eligible if direct bilirubin is within normal limits) * Pulmonary: clinically no evidence of pulmonary disease * Cardiac: no symptoms of uncontrolled cardiac disease * If post-transplant consolidation radiation therapy is given, the patient must be at least 14 days between last radiation treatment and 1st dose of rituximab * Able to take daily aspirin (325 mg) for the duration of INCB7839 treatment and 1 week after the last dose to reduce the risk of thrombosis (not applicable if on other anti-coagulant therapy at time of study enrollment) * Females are either postmenopausal for at least 1 year, are surgically sterile for at least 3 months, or must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through 12 months after the last dose of rituximab if of childbearing potential. (Note: Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed). * Males must agree to take appropriate precautions to avoid fathering a child (with at least 99% certainty) from screening through 12 months after the last dose of rituximab. (Note: Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed). * Voluntary written consent signed before performance of any study-related procedure not part of normal medical care
Exclusion criteria
* Pregnant or lactating - Studies to evaluate the potential for embryo toxicity and teratogenicity have not been performed for INCB7839. Until additional information is available, women of childbearing potential should use appropriate precautions to avoid becoming pregnant. Rituximab is Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Females of childbearing potential must have a negative urine or serum pregnancy test within 14 days of study treatment start * Recent venous thrombosis within 4 weeks prior to study enrollment. Patients at high risk for thrombotic events due to inherited risk factors (i.e. factor V Leiden) or DVT/PE in the past 12 months should be on secondary prophylaxis with anti-coagulant therapy (i.e. warfarin or low molecular weight heparin) prior to enrollment * Active uncontrolled infection * Active CNS disease * Previous severe or life-threatening allergic reaction with rituximab or known allergy to the compounds found in INCB7839 * Any gastrointestinal condition causing malabsorption or obstruction (eg, celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome) * Unwilling or unable to swallow tablets BID * Serologic or clinical evidence of current active hepatitis B or C infection, defined as elevated levels of Hep B antigen or Hep C antibody (unless active infection is ruled out by nucleic acid tests) * Known HIV infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity Events | 2 weeks | The Phase I design will continue until the MTD is declared or until the first dose is declared to be above MTD. Phase I dose limiting toxicity (DLT) is defined as Grade 3-5 non-hematologic, non-infectious toxicity including thromboembolic complications and select hematologic events including: grade 4 neutropenia lasting for ≥ 7 days, febrile neutropenia, grade 4 thrombocytopenia lasting ≥ 7 days despite dose delay or grade 3 thrombocytopenia associated with bleeding. |
| Number of Participants With Progression Free Survival at 6 Months | 6 months | This primary end point will be estimated with Kaplan-Meier curves. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 1 year | To evaluate 1 year overall survival |
| Time to Progression | 1 year | Time to relapse/progression in days |
| Incidence of Serious Adverse Events | 1 year | To determine incidence of serious adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| INCB7839 100 mg (Phase I) Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab
Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later
INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab | 3 |
| INCB7839 200 mg (Phase I) Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab
Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later
INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab | 4 |
| INCB7839 300 mg (Phase I) Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab
Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later
INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab | 7 |
| INCB7839 300 mg (Phase II) Rituximab will be given after day +28 re-staging and again 1 and 7 weeks later, followed by INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab
Rituximab: Rituximab 375 mg/m2 IV after day +28 (as late as day 75) re-staging and again 1 and 7 weeks later
INCB7839: INCB7839 at assigned dose twice daily for 90 days - begin the morning of the 2nd dose of rituximab | 16 |
| Total | 30 |
Baseline characteristics
| Characteristic | INCB7839 100 mg (Phase I) | INCB7839 200 mg (Phase I) | INCB7839 300 mg (Phase I) | INCB7839 300 mg (Phase II) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 3 Participants | 6 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 4 Participants | 10 Participants | 20 Participants |
| Age, Continuous | 59.67 years STANDARD_DEVIATION 4.78 | 59.25 years STANDARD_DEVIATION 8.79 | 53.86 years STANDARD_DEVIATION 14.67 | 57.19 years STANDARD_DEVIATION 11 | 56.93 years STANDARD_DEVIATION 11.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants | 16 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| 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 | 0 Participants | 0 Participants | 0 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 | 3 Participants | 4 Participants | 7 Participants | 16 Participants | 30 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 7 participants | 16 participants | 30 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 2 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 5 Participants | 9 Participants | 17 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 / 3 | 1 / 4 | 2 / 7 | 2 / 16 |
| other Total, other adverse events | 3 / 3 | 3 / 4 | 7 / 7 | 15 / 16 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 1 / 7 | 3 / 16 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity Events
The Phase I design will continue until the MTD is declared or until the first dose is declared to be above MTD. Phase I dose limiting toxicity (DLT) is defined as Grade 3-5 non-hematologic, non-infectious toxicity including thromboembolic complications and select hematologic events including: grade 4 neutropenia lasting for ≥ 7 days, febrile neutropenia, grade 4 thrombocytopenia lasting ≥ 7 days despite dose delay or grade 3 thrombocytopenia associated with bleeding.
Time frame: 2 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INCB7839 100 mg (Phase I) | Number of Participants With Dose Limiting Toxicity Events | 0 Participants |
| INCB7839 200 mg (Phase I) | Number of Participants With Dose Limiting Toxicity Events | 0 Participants |
| INCB7839 300 mg (Phase I) | Number of Participants With Dose Limiting Toxicity Events | 0 Participants |
Primary
Number of Participants With Progression Free Survival at 6 Months
This primary end point will be estimated with Kaplan-Meier curves.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INCB7839 100 mg (Phase I) | Number of Participants With Progression Free Survival at 6 Months | 3 Participants |
| INCB7839 200 mg (Phase I) | Number of Participants With Progression Free Survival at 6 Months | 3 Participants |
| INCB7839 300 mg (Phase I) | Number of Participants With Progression Free Survival at 6 Months | 6 Participants |
| INCB7839 300 mg (Phase II) | Number of Participants With Progression Free Survival at 6 Months | 15 Participants |
Secondary
Incidence of Serious Adverse Events
To determine incidence of serious adverse events
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INCB7839 100 mg (Phase I) | Incidence of Serious Adverse Events | 0 Participants |
| INCB7839 200 mg (Phase I) | Incidence of Serious Adverse Events | 0 Participants |
| INCB7839 300 mg (Phase I) | Incidence of Serious Adverse Events | 1 Participants |
| INCB7839 300 mg (Phase II) | Incidence of Serious Adverse Events | 3 Participants |
Secondary
Overall Survival
To evaluate 1 year overall survival
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INCB7839 100 mg (Phase I) | Overall Survival | 3 Participants |
| INCB7839 200 mg (Phase I) | Overall Survival | 3 Participants |
| INCB7839 300 mg (Phase I) | Overall Survival | 7 Participants |
| INCB7839 300 mg (Phase II) | Overall Survival | 16 Participants |
Secondary
Time to Progression
Time to relapse/progression in days
Time frame: 1 year
Population: Only 3 participants experienced disease progression by 1 year on study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| INCB7839 200 mg (Phase I) | Time to Progression | 105 days |
| INCB7839 300 mg (Phase I) | Time to Progression | 136 days |
| INCB7839 300 mg (Phase II) | Time to Progression | 259 days |