Pneumococcal Pneumonia Vaccine Series (PCV20 and PPSV23) in Patients With Chronic Lymphocytic Leukemia Associated Immunodeficiency, PROTECT CLL Trial

Study Overview
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Brief Summary
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This phase II trial tests whether the pneumococcal pneumonia vaccine series (PCV20 and PPSV23) works to mount an effective immune response in patients with chronic lymphocytic leukemia. PCV20 and PPSV23 are both vaccines that protect against bacteria that cause pneumococcal disease. Giving these vaccinations as series may make a stronger immune response and prevent against pneumococcal infections in patients with chronic lymphocytic leukemia.

Detailed Description
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PRIMARY OBJECTIVE: I. To investigate the proportion of chronic lymphocytic leukemia (CLL) patients who mount an effective immune response to streptococcus pneumonia after receiving both pneumococcal 20-valent conjugate vaccine (PCV20) and pneumococcal polyvalent vaccine (PPSV23) vaccinations. (Primary Analysis) SECONDARY OBJECTIVES: I. To improve the immunoglobulin levels and decrease the incidence of pneumonia in patients with CLL-associated immunodeficiency. (Primary Analysis) II. To evaluate the rate of decreased pneumonia as assessed by an immune response to streptococcus (S.) pneumoniae after PCV20 and PPSV23 series versus PCV20 alone. (Primary Analysis) III. To investigate the immune response to individual S. pneumoniae serotypes included in both the PCV20 and PPSV23 vaccinations. (Primary Analysis) IV. Evaluate the length of time an effective immune response is maintained, and if the recommendation of 5 years is adequate for CLL patients. (Primary Analysis) EXPLORATORY OBJECTIVES: I. Assess rate of pneumonia in CLL patients based on therapeutic strategy (i.e., BTKi, venetoclax, chemo-immunotherapy). II. To evaluate the number of venetoclax treated CLL patients who mount an effective immune response to S. pneumoniae 30 days following both PCV20 and PPSV23 vaccinations. (Pilot Arm) OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (PRIMARY ARM): Patients receive pneumococcal 20-valent conjugate vaccine intramuscularly (IM) on day 1 and pneumococcal polyvalent vaccine IM on day 60 in the absence of disease progression or unacceptable toxicity. ARM II (PILOT ARM): Patients who have received or are receiving venetoclax therapy, receive pneumococcal 20-valent conjugate vaccine IM on day 1 and pneumococcal polyvalent vaccine IM on day 60 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 90 days and then every 6 months for 5 years.

Official Title
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Phase II Study of the Efficacy of the Pneumococcal Pneumonia Vaccine Series in Patients With Chronic Lymphocytic Leukemia Associated Immunodeficiency (PROTECT CLL)

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Biological: Pneumococcal 20-valent Conjugate Vaccine
* Biological: Pneumococcal Polyvalent Vaccine
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NAIVE COHORT: Subjects must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout) according to the 2018 International Workshop on CLL. NAIVE COHORT: Male or female subject aged >= 18 years. NAIVE COHORT: Subjects must not have received prior therapy for CLL. VENETOCLAX-TREATMENT COHORT: Subjects must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (collectively referred to as CLL throughout) according to the 2018 International Workshop on CLL. VENETOCLAX-TREATMENT COHORT: Subjects must have received venetoclax (any dose) for at least 12 months with the last dose =< 12 months prior to registration. Exclusion Criteria: Subjects who have experienced a severe allergic reaction to prior pneumococcal vaccination. Subjects who have received a PCV13 or PCV20 pneumococcal vaccination in the last five years. If they have received PPSV23 in ≥ 1 year and no other pneumococcal vaccine they may be included. Active infection requiring systemic antibiotic therapy. Current or prior use of immunosuppressive medication within 14 days of cycle one day one, EXCEPT for the following permitted steroids: Intranasal, inhaled, topical steroids, eye drops or local steroid injection (e.g., intra-articular injection); Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication). Concurrent illness or condition, which, in the opinion of the treating investigator, would negatively impact the subject's study participation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (PCV20, PPSV23)<br>Patients receive pneumococcal 20-valent conjugate vaccine IM on day 1 and pneumococcal polyvalent vaccine IM on day 60 in the absence of disease progression or unacceptable toxicity. | Biological: Pneumococcal 20-valent Conjugate Vaccine<br>* Given IM<br>* Other names: Prevnar 20;Biological: Pneumococcal Polyvalent Vaccine<br>* Given IM<br>* Other names: PPSV23 Vaccine;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (PCV20, PPPSV23)<br>Patients who have received or are receiving venetoclax therapy, receive pneumococcal 20-valent conjugate vaccine IM on day 1 and pneumococcal polyvalent vaccine IM on day 60 in the absence of disease progression or unacceptable toxicity. | Biological: Pneumococcal 20-valent Conjugate Vaccine<br>* Given IM<br>* Other names: Prevnar 20;Biological: Pneumococcal Polyvalent Vaccine<br>* Given IM<br>* Other names: PPSV23 Vaccine;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who achieve the protocol defined change in antibody titers | Will examine the proportion of patients who achieve the protocol defined change in antibody titers from baseline in at least 6 of 12 S.pneumoniae serotypes shared between pneumococcal 20-valent conjugate vaccine (PCV20) and pneumococcal polyvalent vaccine (PPSV23) at 30 and 90 days post-PCV20 vaccination. The observed proportion and an exact 95% binomial confidence interval will be reported. A one sample exact binomial test will be performed at one-sided alpha = 0.05. The null hypothesis is that the proportion is 50% or lower. | At 30 and 90 days post-PCV20 vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have a two-fold increase of immunoglobulin levels | Will examine the proportion of patients who have a two-fold increase of immunoglobulin levels from baseline at 30 and 90 days and do not develop pneumonia within five years post-PPSV23 vaccination. The observed proportion and an exact 95% binomial confidence interval will be reported. | Up to 5 years post- PPSV23 vaccination | 
| Proportion of vaccinated patients who have a two-fold increase in at least 6 of 12 S. pneumonia serotypes shared between PCV20 and PPSV23 vaccines | Will examine the proportion of vaccinated patients who have a two-fold increase in at least 6 of 12 S. pneumonia serotypes shared between PCV20 and PPSV23 vaccines and do not develop pneumonia within five years post PPSV23 vaccination. The observed proportion and an exact 95% binomial confidence interval will be reported. | Up to 5 years post PPSV23 vaccination | 
| Proportion of patients who have a two-fold increase in antibody titers to an individual serotype vaccination | Will examine the proportion of patients who have a two-fold increase in antibody titers to an individual serotype at 30 and 90 days post PPCV20 vaccination. The observed proportion and 95% exact binomial confidence intervals will be reported for each serotype. | At 30 and 90 days post-PCV20 vaccination | 
| Proportion of patients who maintain adequate immune response | Will examine the proportion of patients who maintain adequate immune response, defined as two-fold increase in antibody titers from baseline in 6/12 of S. pneumoniae serotypes, from PPSV23 vaccination to time of last follow-up at 5 years. Kaplan-Meier methods will be used to analyze time-to-pneumonia from baseline until five years after PPSV23 vaccination. | Up to 5 years post PPSV23 vaccination |