IRB Study Number 24-985
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
1.1.1 To compare the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL who have a rapid early response (RER) as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy.
1.1.2 To compare the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) plus involved site radiation therapy (ISRT) in patients with newly diagnosed early stage cHL who have a slow early response (SER) as determined by PET2 after 2 cycles of ABVD chemotherapy.
1.2 Secondary Objectives
1.2.1 To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a RER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy.
1.2.2 To evaluate the overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a SER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy.
1.2.3 To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients.
1.2.4 To evaluate in patients with newly diagnosed early stage cHL the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in the overall cohort, in the favorable risk cohort, and in the unfavorable risk cohort.
1.2.5 To evaluate the EFS at 12 years of patients undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab).
1.2.6 To compare the physician-reported treatment-related adverse event (AE) rates between a standard chemotherapy approach and an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL.
1.2.7 To compare patient-reported adverse events using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), stratified by age groups, therapeutic arms, and receipt of RT over time.
1.2.8 To evaluate changes in patient-reported fatigue, cognitive functioning, and health-related quality of life (HRQoL), e.g., emotional, physical, and role functioning, by treatment arm, using validated adult and pediatric measurement systems.
1.2.9 To evaluate self-reported late morbidities (e.g., cardiovascular, pulmonary and endocrine) over time for children, adolescents and adults undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab) with and without RT using measures from the St. Jude Lifetime Cohort Study (SJLIFE).
1.2.10 To evaluate FDG-PET measurements of metabolic tumor burden (MTV and TLG) at PET1 as a predictive marker of PFS.
1.2.11 To evaluate the associations between race/ethnicity and key outcomes including early response to therapy, PFS and OS.
Inclusion Criteria
3.2.1 Age
Patients must be 5 to 60 years of age at the time of enrollment.
3.2.2 Diagnosis
3.2.2.1 Patients with newly diagnosed untreated histologically confirmed classic Hodgkin lymphoma (cHL) (nodular sclerosis, mixed cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified (NOS)) with Stage I or II disease.
3.2.2.2 Patients must have bidimensionally measurable disease (at least one lesion with longest diameter ≥ 1.5 cm).
3.2.2.3 Patients must have a whole body or limited whole body PET scan performed within 42 days prior to enrollment. PET-CT is strongly preferred. PET-MRI allowed if intravenous contrast enhanced CT is also obtained.
3.2.2.4 Pediatric patients (age 5-17 years) must have an upright PA CXR for assessment of bulky mediastinal disease. Adult patients must have either a CXR or CT chest.
3.2.3 Performance Score
• Patients ≥ 18 years must have a performance status corresponding to Zubrod scores of 0, 1 or 2.
• Patients ≤ 17 years of age must have a Lansky performance score of ≥ 50.
See Appendix IV for details.
3.2.4 Organ Function Requirements
Please note that eligibility criteria and the timing of documentation prior to enrollment differ by age.
3.2.4.1 Adequate renal function defined as:
• For pediatric patients (age 5-17 years):
- A serum creatinine* based on age/gender as follows: (See protocol)
OR - a 24 hour urine Creatinine clearance ≥ 50 mL/min/1.73 m2
OR - a GFR ≥ 50 mL/min/1.73 m2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
• For adult patients (age 18 years or older):
Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight.
Estimated creatinine clearance = (140 - age) x weight in kg †
72 x creatinine* (mg/dl)
Multiply this number by 0.85 if the participant is a female.
† The kilogram weight is the participant weight with an upper limit of 140% of the ideal body weight (IBW).
* Actual lab serum or plasma creatinine value with a minimum of 0.7 mg/dL.
3.2.4.2 Adequate liver function* defined as:
• Total bilirubin ≤ 2 x ULN, and
• AST and ALT ≤ 3 x ULN
* unless due to Gilbert’s disease, lymphomatous involvement of liver or vanishing bile duct syndrome
3.2.4.3 Adequate cardiac function defined as:
Shortening fraction of ≥ 27% by echocardiogram (ECHO), MUGA, or functional cardiac imaging scan or
Ejection fraction of ≥ 50% by radionuclide angiogram, ECHO, MUGA, or cardiac imaging scan.
3.2.4.4 Adequate pulmonary function defined as:
DLCO ≥ 50% of predicted value as corrected for hemoglobin by pulmonary function test (PFT)
If unable to obtain PFTs, the criterion is: a pulse oximetry reading of > 92% on room air.
3.2.5 HIV Status
Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
3.2.6 HBV and HCV Status
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Exclusion Criteria
3.2.7 Patients with nodular lymphocyte predominant Hodgkin Lymphoma.
3.2.8 Patients with a history of active interstitial pneumonitis or interstitial lung disease.
3.2.9 Patients with a diagnosis of inherited or acquired immunodeficiency that is poorly controlled or requiring active medications, such as primary immunodeficiency syndromes or organ transplant recipients
3.2.10 Patients with any known uncontrolled intercurrent illness that would jeopardize the patient’s safety such as infection, autoimmune conditions, cardiac arrhythmias, angina pectoris, and gastrointestinal disorders affecting swallowing and/or absorption of pills.
3.2.11 Patients with a condition requiring systemic treatment with either corticosteroids (defined as equivalent to > 10 mg daily prednisone for patients ≥ 18 years or > 0.5 mg/kg (up to 10 mg/day) for patients < 18 years) or other immunosuppressive medications within 14 days prior to enrollment.
Note: Replacement therapy such as thyroxine, insulin, or physiologic corticosteroid for adrenal or pituitary insufficiency is not considered a form of systemic treatment. Inhaled or topical steroids, and adrenal replacement doses (≤ 10 mg daily for patients ≥ 18 years or ≤ 0.5 mg/kg (up to 10 mg/day) prednisone equivalents are permitted in the absence of active autoimmune disease.
Note: Steroid use for the control of Hodgkin lymphoma symptoms is allowable, but must be discontinued by Cycle 1, Day 1.
3.2.12 Patients with peripheral neuropathy > Grade 1 at the time of enrollment or patients with known Charcot-Marie-Tooth syndrome.
3.2.13 Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.
3.2.14 Prior Therapy
3.2.14.1 Administration of prior chemotherapy, radiation, or antibody-based treatment for cHL.
3.2.14.2 Prior solid organ transplant.
3.2.14.3 Prior allogeneic stem cell transplantation.
3.2.14.4 Live vaccine within 30 days prior to planned Day 1 of protocol therapy (e.g., measles, mumps, rubella, varicella, yellow fever, rabies, BCG, oral polio vaccine, and oral typhoid). Administration of mRNA vaccines are permitted.
Please see Section 4.1 for the concomitant therapy restrictions for patients during treatment.
3.2.15 Pregnancy and Breastfeeding,
3.2.15.1 Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test within 28 days prior to enrollment is required for female patients of childbearing potential.
3.2.15.2 Lactating females who plan to breastfeed their infants starting with the first dose of study therapy and for at least 6 months after the last treatment.
3.2.15.3 Sexually active patients of reproductive potential who have not agreed to use a highly effective contraceptive method (failure rate of < 1% per year when used consistently and correctly) for the duration of their study drug therapy. Following therapy, patients will be advised to use contraception as per institutional practice or as listed below for investigational agents, whichever is longer.
Men and women of childbearing potential must continue contraception for a period of 6 months after last dose of brentuximab vedotin.
Women of child-bearing potential (WOCBP) must continue contraception for a period of at least 5 months after the last dose of nivolumab.
3.2.16 Regulatory Requirements
3.2.16.1 All patients and/or their parents or legal guardians must sign a written informed consent.
3.2.16.2 All institutional, FDA, and NCI requirements for human studies must be met.
