Peripheral T Cell Lymphoma
Conditions
Keywords
Nivolumab, First Line Treatment, EPOCH, Standard of Care
Brief summary
This regimen aims to become the first line treatment for peripheral T cell lymphoma, using nivolumab with the standard of care chemotherapy.
Detailed description
Patients in this study will receive nivolumab in combination with the standard of care dose-adjusted EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) for six 21 day cycles. Patients will then have an autologous stem cell transplant or continue to receive maintenance therapy with nivolumab.
Interventions
DRUGNivolumab
Nivolumab injection is to be administered as an IV infusion.
DRUGEtoposide
Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.
DRUGPrednisolone
Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.
DRUGOncovin
Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.
DRUGCyclophosphamide
Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.
Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a \>10% weight gain or loss. Patients receive six 21-day cycles of the medications.
Sponsors
Bristol-Myers Squibb
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Ability to sign and date the consent form. 2. Stated willingness to comply with all study procedures and be available for the duration of the study. 3. Be a male or female aged 18-80. 4. Histologically confirmed new diagnosis of Stage II, III or IV Peripheral T-cell Non-Hodgkin's lymphoma not otherwise specified (NOS), Anaplastic large cell lymphoma (ALK-negative) (ALK-positive if IPI 3, 4, or 5), Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell lymphoma (MEITL and EATL), Hepatosplenic T-cell lymphoma, y/8 T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, and Nodal T-cell lymphomas with T-follicular helper phenotype. 5. Available pathology material (fine needle aspirate is inadequate) for review at the University of Colorado. 6. No prior therapy with the exception of prior radiation therapy and/or 1 cycle of chemotherapy (may be any chemotherapy regimen or even prednisone alone) based on current diagnosis and clinical condition. If given cytotoxic chemotherapy (one cycle only, e.g. CHOP), this cycle of treatment will count toward the 6 cycles of treatment given in the study. 7. ECOG performance status 0 - 2. 8. Laboratory status as follows: * ANC \> 1000 cells/mm3, unless cytopenias due to lymphoma (i.e., bone marrow involvement or splenomegaly) * Platelet Count \> 100,000 /μL, or \> 50,000 /μL if bone marrow involvement or splenomegaly * Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if documented hepatic involvement with lymphoma, or ≤ 5 x upper normal limit if history of Gilbert's Disease. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (≤ 5 x upper normal limit if documented hepatic involvement with lymphoma). * Serum creatinine \< 2.0 mg/dL or calculated creatinine clearance (CrCl) \> 45 mL/min (Cockcroft-Gault, Appendix) * PT or INR, and PTT ≤ 1.5 x upper limit of normal unless patient is receiving anticoagulants. If patient is on warfarin therapy, levels should be within therapeutic range. 9. Patients with measurable disease. Measurable disease is defined as having at least one objective measurable disease parameter. A clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on the CT portion of a PET/CT or CT scan or MRI (if appropriate) will constitute measurable disease. Proof of lymphoma in the liver is required by a confirmation biopsy unless there is measurable disease by imaging. Skin lesions can be used as measurable disease provided bi-dimensional measurements are possible. Patients with non-measurable but evaluable disease may be eligible after discussion with the PI. Abnormal PET/CT scans will not constitute evaluable disease, unless verified by the CT scan portion, CT scan, or other appropriate imaging. 10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. 11. Patient must be able to adhere to the study visit schedule and other protocol requirements.
Exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study: 1. An additional malignancy treated with palliative intent within the past 2 years. Malignancies in patients who have completed definitive treatment with curative intent \>1 year will be permitted after discussion with the PI. Adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Grade 6 or less with stable PSA levels are allowed. 2. Patients with a diagnosis of other PTCL histologies other than those specified in the inclusion criteria. 3. Primary T-cell CNS lymphoma; however, secondary CNS disease is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Complete Response Rate | up to 100 days post transplant | Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | up to 100 days after last dose of nivolumab | Toxicity analysis of nivolumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 and relationship to study drug or the amount of grade 4-5 non-hematologic toxicities. |
| Efficacy: Overall Response Rate | up to 100 days post transplant | Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. Complete response (CR), complete disappearance of all target lesions and Deauville score 1-3. Partial response (PR), ≥30% decrease in the sum of longest diameters of target lesions but not a CR and Deauville score 4-5. Stable disease (SD), \<30% decrease or ≤ 20% increase in the sum of longest diameters of target lesions. Progressive disease (PD), \>20% increase in the sum of longest diameters of target lesions, For small lymph nodes measuring \< 15 mm post-therapy, a minimum of 5 mm increase in longest diameter to \> 15 mm, or new lesions. |
| Efficacy: Progression Free Survival Rate | up to 2 years after completion of treatment | Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. |
| Efficacy: Event Free Survival | up to 2 years after completion of treatment | Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. Events defined as start of new treatment, progression, or death. |
| Immune-related Predictors of Response | Within 6 months of treatment | We assessed PD-L1 expression using immunohistochemistry on pre-treatment tumor tissue. The outcome of measurement was complete response yes vs. no. Using logistic regression, we assessed if the percentage of PDL1+ cells was predictive of achieving a complete response. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab and EPOCH Patients will all receive nivolumab in combination with standard dose adjusted EPOCH for a planned 6 cycles, unless treatment is stopped early for disease progression or toxicity. Patients that have already received up to 1 cycle of standard of care chemotherapy will receive 5 cycles of experimental nivolumab + DA-EPOCH (dose adjusted, continuous infusion etoposide, prednisone, vincristine, doxorubicin, and bolus dosing of cyclophosphamide) for a total of 6 cycles of chemotherapy. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 2 |
Baseline characteristics
| Characteristic | Nivolumab and EPOCH |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 63.16 years STANDARD_DEVIATION 10.43 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 18 |
| other Total, other adverse events | 18 / 18 |
| serious Total, serious adverse events | 13 / 18 |
Outcome results
Primary
Efficacy: Complete Response Rate
Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.
Time frame: up to 100 days post transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab and EPOCH | Efficacy: Complete Response Rate | 11 Participants |
Comparison: The study was to be suspended, if, at any time, there was sufficient evidence to suggest that the true probability of achieving a complete response falls below 30% while assuming the treatment drug will elicit a 56% complete response rate. Statistically significant evidence for this low complete response rate is defined as an observed complete response rate whose upper one-sided 90% confidence limit is 0-30%. Sample size calculations were made assuming 80% power.p-value: 0.1t-test, 2 sided
Secondary
Efficacy: Event Free Survival
Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. Events defined as start of new treatment, progression, or death.
Time frame: up to 2 years after completion of treatment
Population: All patients treated on trial
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab and EPOCH | Efficacy: Event Free Survival | 10.5 months |
Secondary
Efficacy: Overall Response Rate
Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy. Complete response (CR), complete disappearance of all target lesions and Deauville score 1-3. Partial response (PR), ≥30% decrease in the sum of longest diameters of target lesions but not a CR and Deauville score 4-5. Stable disease (SD), \<30% decrease or ≤ 20% increase in the sum of longest diameters of target lesions. Progressive disease (PD), \>20% increase in the sum of longest diameters of target lesions, For small lymph nodes measuring \< 15 mm post-therapy, a minimum of 5 mm increase in longest diameter to \> 15 mm, or new lesions.
Time frame: up to 100 days post transplant
Population: All patients on trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab and EPOCH | Efficacy: Overall Response Rate | 16 Participants |
Secondary
Efficacy: Progression Free Survival Rate
Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.
Time frame: up to 2 years after completion of treatment
Population: All patients treated on trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab and EPOCH | Efficacy: Progression Free Survival Rate | 14.5 months |
Secondary
Immune-related Predictors of Response
We assessed PD-L1 expression using immunohistochemistry on pre-treatment tumor tissue. The outcome of measurement was complete response yes vs. no. Using logistic regression, we assessed if the percentage of PDL1+ cells was predictive of achieving a complete response.
Time frame: Within 6 months of treatment
Population: Only 17 participants had tumor tissue available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nivolumab and EPOCH | Immune-related Predictors of Response | 0.985 odds ratio |
Secondary
Number of Participants With Adverse Events
Toxicity analysis of nivolumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 and relationship to study drug or the amount of grade 4-5 non-hematologic toxicities.
Time frame: up to 100 days after last dose of nivolumab
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nivolumab and EPOCH | Number of Participants With Adverse Events | 18 Participants |