Fitness-Adapted, Pembrolizumab-Based Therapy for the Treatment of Untreated Classical Hodgkin Lymphoma in Patients 60 Years of Age and Above
This phase II trial tests whether fitness-adapted, pembrolizumab-based therapy works in treating patients 60 years or age or above with untreated classical Hodgkin lymphoma. A common treatment for classical Hodgkin Lymphoma often includes four drugs: Adriamycin (A), vinblastine (V), and dacarbazine (D), and brentuximab vedotin. This treatment can be difficult to tolerate and can result in long term side effects. Difficulty with the treatment is more common with patients who are over the age of 60 and unfit. Doctors will sometimes treat unfit or elderly patients with only the brentuximab vedotin drug to prevent dangerous side effects from the AVD drugs. This treatment with brentuximab vedotin alone has not been shown to be as effective as treatment with all four drugs. There are currently no guidelines on how doctors should make the decision to only treat with brentuximab vedotin or to use all drugs. This study is trying to find out if fitness assessments can help doctors decide what type of treatment is best for classical Hodgkin lymphoma patients over the age of 60 with different levels of fitness. This study will also help determine if a study drug, pembrolizumab, is effective as part of the upfront treatment regimen of classical Hodgkin lymphoma.
Inclusion Criteria
- Individuals 60 years of age or older with treatment-naive, histologically-proven classical Hodgkin lymphoma (according to World Health Organization [WHO] Haematolymphoid tumors 5th edition [HAEM5], or ICL classification)
- Participants of any sex who are >= 60 years of age on day 1, cycle 1
- The participant must be willing and able to provide written informed consent for the trial and participate in all planned study procedures
- Histologically confirmed diagnosis of classical Hodgkin lymphoma
- PET-avid, measurable disease (>= 1.5cm bi-dimensional measurement)
- Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. PS 2 may be allowed at the discretion of the treating investigator if impairment is considered to be primarily lymphoma-related. Evaluation of ECOG is to be performed within 10 days prior to the date of registration
- Participants who have received involved field radiation will be allowed. However, they will be excluded if any of the following are true: * Radiation was dosed =< 6 months from registration * Radiation was delivered to > 1 lymph node group as defined by the National Comprehensive Cancer Network (NCCN) criteria * The radiation dose was >= 30 Gy * The participant has radiation-related toxicities >= Grade 2 at the time of registration * The participant requires corticosteroids for radiation-related toxicities at the time of registration (regardless of dose) * The participant has ever experienced radiation pneumonitis
- Absolute neutrophil count (ANC) >= 1500/uL (>= 1000/uL if due to cHL) (collected within 10 days prior to registration)
- Platelets >= 100 000/uL (>= 75 000/ul if due to cHL) (collected within 10 days prior to registration)
- Hemoglobin >= 8.0 g/dL (collected within 10 days prior to registration)
- Measured or calculated creatinine clearance or measured glomerular filtration rate (GFR) >= 30 mL/min (collected within 10 days prior to registration) * Creatinine clearance (CrCl) should be calculated per the Cockcroft-Gault formula * If standard of care work up includes nuclear medicine evaluation of GFR, this can be used for study entry instead of calculated CrCl
- Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (collected within 10 days prior to registration)
- Alanine aminotransferase (AST) (serum glutamic pyruvic transaminase [SGOT]) and aspartate aminotransferase (ALT) (serum glutamic oxaloacetic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (collected within 10 days prior to registration)
- Thyroid stimulating hormone (TSH) within normal limits, OR both T3 and free T4 within normal limits (for participants with abnormal TSH) (collected within 10 days prior to registration)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (if participant is receiving anticoagulant therapy, this criteria will be met as long as PT is within therapeutic range of intended use of anticoagulants) (collected within 10 days prior to registration)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (if participant is receiving anticoagulant therapy, this criteria will be met as long as aPTT is within therapeutic range of intended use of anticoagulants) (collected within 10 days prior to registration)
Exclusion Criteria
- Nodular lymphocyte-predominant Hodgkin lymphoma by WHO-HAEM5 or Nodular lymphocyte predominant B-cell lymphoma by ICL classification
- Life expectancy < 6 months for any reason excluding lymphoma
- Has received prior therapy with an immune checkpoint inhibitor, against targets including but not limited to PD1, PDL1, PDL2, CTLA-4, OX40, or LAG 3 unless given with curative intent for reasons other than lymphoma AND the last dose was more than 3 years from registration. Any participant who received prior immune checkpoint inhibitor therapy will be excluded if they experienced any toxicity related to or possibly related to the immunotherapy that required discontinuation of drug
- Prior systemic therapy for cHL, with the exception of steroids
- If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
- Presence of Grade >= 2 sensory and/or motor neuropathy
- Prior solid organ or stem cell transplant
- Clinical suspicion or evidence of active involvement of lymphoma into the spinal cord, cerebral spinal fluid, or brain. External compression of the spinal cord or nerve roots is not considered involvement
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines, subunit vaccines, and nucleic acid vaccines is allowed
- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent [excluding steroids needed for lymphoma related symptoms]) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (excluding carcinoma in situ of the bladder) that have undergone potentially curative therapy are not excluded
- Has known severe hypersensitivity (>= Grade 3) to pembrolizumab and/or any of its excipients
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Interstitial lung disease or a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
- Any known history of pancreatitis as defined by Gandhi et al. 2014
- Has an active infection requiring oral or intravenous systemic therapy
- Has a known history of Human Immunodeficiency Virus (HIV)
- Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Prior exposure to hepatitis B is allowed as long as there are no HBsAg detected (i.e., positive Hepatitis B core antibody with negative HBsAg). Prior treatment with Hepatitis C is allowed if the screening HCV RNA by polymerase chain reaction (PCR) is negative
- Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis)
- Is currently taking a strong CYP3A4 modulator. Subjects taking strong CYP34A modulators that can safely stop these medications prior to treatment should complete a washout period of 4 weeks or 5 times the half-life of a particular drug, whichever is shorter
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment * Note: given older age at enrollment, women of child bearing potential (WOCBP) are not anticipated to enroll on this study
Additional locations may be listed on ClinicalTrials.gov for NCT05404945.
Locations matching your search criteria
United States
New Jersey
New Brunswick
Pennsylvania
Philadelphia
Virginia
Charlottesville
PRIMARY OBJECTIVE:
I. To assess the safety and efficacy of a fitness-adapted pembrolizumab-based regimen in untreated older patients with classical Hodgkin lymphoma (cHL).
SECONDARY OBJECTIVES:
I. To assess the long-term disease control and survival in the fit and unfit older population following pembrolizumab-based adaptive therapy.
II. To assess the long-term disease control and survival of a chemotherapy-free approach (pembrolizumab plus brentuximab vedotin [BV]) in participants who are frail.
III. To assess efficacy of short course lead-in therapy and correlation with end-induction treatment efficacy for all participants.
IV. To assess safety, as determined by the frequency of higher-grade immune-related adverse events, following a fitness-adapted pembrolizumab-based regimen in untreated older patients with cHL.
EXPLORATORY OBJECTIVES:
I. To assess the rate of “indeterminate response” by Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) at interim and end-induction positron emission tomography/computed tomography (PET/CT) and correlate with the presence of active Hodgkin lymphoma on biopsy (when available) and clinical outcomes.
II. To evaluate changes in fitness assessments throughout therapy, including an evaluation of the predictive potential of pre-therapy assessment compared to the fitness assessment after lead-in pembrolizumab and BV.
III. To summarize participant fitness throughout therapy by incidence and severity of treatment-related toxicities.
IV. To characterize and evaluate lymphocytic populations in the periphery and summarize by tolerability and efficacy of immune-based therapy.
OUTLINE: Patients are assigned to 1 of 3 groups.
GROUP I (FIT):
LEAD-IN: Patients receive brentuximab vedotin intravenously (IV) on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1.
INDUCTION: Patients receive standard chemotherapy drugs consisting of doxorubicin IV, vinblastine IV, and dacarbazine IV on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab on day 1 of each cycle. Cycles repeat every 6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION AND MAINTENANCE: Patients receive brentuximab vedotin IV on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
GROUP II (NON-FIT):
LEAD-IN: Patients receive brentuximab vedotin IV on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1.
INDUCTION: Patients receive doxorubicin IV, vinblastine IV and dacarbazine IV on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab on day 1 of each cycle. Cycles repeat every 6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION AND MAINTENANCE: Patients receive brentuximab vedotin IV on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
GROUP III (FRAIL):
LEAD-IN: Patients receive brentuximab vedotin IV on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1.
INDUCTION: Patients receive brentuximab vedotin IV on day 1 and 22 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION AND MAINTENANCE: Patients receive brentuximab vedotin IV on day 1 and 22 of cycle 1 and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Patients also undergo collection of blood during screening and on study, and magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT) throughout the trial.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Virginia Cancer Center
Principal InvestigatorCraig Anthony Portell
- Primary IDHSR210534
- Secondary IDsNCI-2022-07530, CHL001
- ClinicalTrials.gov IDNCT05404945