A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Allogeneic Hematopoietic Stem Cell Transplant Recipients (V114-022/PNEU-STEM)

Study Overview
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Brief Summary
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The purpose of this study is to 1) evaluate the safety and tolerability, and immunogenicity of blinded V114 and Prevnar 13™ within each vaccination group, and 2) evaluate the safety and tolerability, and immunogenicity of PNEUMOVAX™23 (administered as open label, 12 months after allogeneic hematopoietic stem cell transplant [allo-HSCT] in participants who do not develop chronic graft-versus-host disease [GVHD]).

Official Title
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A Phase 3, Randomized, Double-blind, Active Comparator-controlled, Multicenter Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Recipients of Allogeneic Hematopoietic Stem Cell Transplant (PNEU-STEM)

Conditions
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Pneumococcal Infections

Intervention / Treatment
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* Biological: V114
* Biological: Prevnar 13™
* Biological: PNEUMOVAX™23


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Received a human leukocyte antigen (HLA) compatible donor including haploidentical and mismatched (related or unrelated) first allogeneic HSCT (i.e., bone marrow or peripheral blood stem cell) 90 to 180 days prior to randomization. Received the allogeneic HSCT for acute lymphoblastic leukemia (ALL) in first or second remission, acute myeloid leukemia (AML) in first or second remission, chronic myeloid leukemia (CML) in first chronic or accelerated phase, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome (MDS), myelofibrosis and myeloproliferative diseases, and non-malignant disease such as aplastic anemia or sickle cell disease in participants ≥18 years of age and any non-malignant disease for participants 3 to <18 years of age. Life expectancy >12 months after allogeneic HSCT, according to investigator judgement. Clinically stable engraftment according to investigator judgment. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies: a) not a woman of childbearing potential (WOCBP) OR b) a WOCBP who agrees to use acceptable contraceptive methods during the treatment period and for at least 6 weeks after the last dose of study intervention. Exclusion Criteria: Receipt of a previous allogeneic HSCT. Received allogeneic HSCT with ex-vivo graft manipulation, in vivo T cell depletion with alemtuzumab, or haploidentical allogeneic HSCT with high dose anti-thymocyte globulin. Received allogeneic HSCT for multiple myeloma or, for participants ≥18 years of age only, for any nonmalignant diseases except sickle cell disease and aplastic anemia. Persistent or relapsed primary disease after allogeneic HSCT. History of severe GVHD (Grade 3 or 4 GVHD) after allogeneic HSCT. Planned organ transplantation after allogeneic HSCT. History of culture-positive pneumococcal disease occurring after allogeneic HSCT. Known hypersensitivity to any component of pneumococcal polysaccharide vaccine, pneumococcal conjugate vaccine, or any diphtheria toxoid-containing vaccine. History of acquired immunodeficiency such as documented HIV infection, or anatomic asplenia. Coagulation disorder contraindicating intramuscular vaccinations. Severe hepatic impairment (defined as Child-Pugh Class C) at Screening. Serum aspartate transaminase (AST) or alanine transaminase (ALT) >6 × upper limit of normal (ULN) or serum total bilirubin >2.5 × ULN at Screening. A WOCBP who has a positive urine or serum pregnancy test before the 1st vaccination. Received chimeric antigen receptor T-cell (CAR-T) therapy or checkpoint inhibitor directed therapy (i.e., anti-Programmed Cell Death (PD)-1) after allogeneic HSCT. Received or planned to receive anti-Cluster of Differentiation (CD) 20 B-cell targeted therapy (e.g., rituximab) after allogeneic HSCT. Non-study pneumococcal vaccine administered after allogeneic HSCT, or is expected to receive non-study pneumococcal vaccine during participation in the study. Is currently participating or has participated in an interventional clinical study with an investigational compound/agent or device within 2 weeks of participating in this current study, or plans to receive any investigational compound/agent or device (in addition to existing therapy) within 2 weeks of any vaccination, that in the opinion of the investigator would interfere with the evaluation of the study objectives. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence as assessed by the study investigator. Has history or current evidence of any condition, therapy, laboratory test result abnormality, or other circumstance that might expose the participant to risk by participating in the study, confound the results of the study, or interfere with the participant's participation for the full duration of the study. Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study.

Ages Eligible for Study
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Minimum Age: 3 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V114<br>Participants will receive a single 0.5 mL intramuscular (IM) injection of V114 on Day 1, Day 30 and Day 60 and a single 0.5 mL IM injection of PNEUMOVAX™23 at 12 months after HSCT. Participants will have received HSCT 90 to 180 days prior to Day 1. Those who develop chronic graft-versus-host-disease (GVHD) during the first year after HSCT will receive V114 instead of PNEUMOVAX™23 as their fourth dose. | Biological: V114<br>* 15-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, 33F (2 mcg each), serotype 6B (4 mcg) and Merck Aluminum Phosphate Adjuvant (125 mcg) in each 0.5 mL dose.<br>* Other names: Pneumococcal 15-Valent Conjugate Vaccine;Biological: PNEUMOVAX™23<br>* 23-valent pneumococcal polysaccharide vaccine with serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F (25 mcg each) in each 0.5 mL dose<br>|
| Active Comparator: Prevnar 13™<br>Participants will receive a single 0.5 mL IM injection of Prevnar 13™ on Day 1, Day 30 and Day 60 and a single 0.5 mL IM injection of PNEUMOVAX™23 at 12 months after HSCT. Participants will have received HSCT 90 to 180 days prior to Day 1. Those who develop chronic GVHD during the first year after HSCT will receive Prevnar 13™ instead of PNEUMOVAX™23 as their fourth dose. | Biological: Prevnar 13™<br>* 13-valent pneumococcal conjugate vaccine with serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F (2.2 mcg) and 6B (4.4 mcg), and aluminum phosphate adjuvant (125 mcg aluminum) in each 0.5 ml dose<br>Biological: PNEUMOVAX™23<br>* 23-valent pneumococcal polysaccharide vaccine with serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F (25 mcg each) in each 0.5 mL dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult Participants: Percentage of Participants With a Solicited Injection-site Adverse Event Following Any of the First 3 Doses With V114 or Prevnar 13™ | An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following any of the first 3 doses of V114 or Prevnar 13™, the percentage of adult participants with solicited injection-site AEs was assessed. The solicited injection-site AEs were erythema, pain, and swelling. | Up to 5 days after any of the Day 1, Day 30, or Day 60 vaccinations (V114 or Prevnar 13™) | 
| Pediatric Participants: Percentage of Participants With a Solicited Injection-site Adverse Event Following Any of the First 3 Doses With V114 or Prevnar 13™ | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following any of the first 3 doses of V114 or Prevnar 13™, the percentage of pediatric participants with solicited injection-site AEs was assessed. The solicited injection-site AEs were erythema, induration, pain, and swelling. | Up to 14 days after any of the Day 1, Day 30, or Day 60 vaccinations (V114 or Prevnar 13™) | 
| Adult Participants: Percentage of Participants With a Solicited Systemic Adverse Event Following Any of the First 3 Doses With V114 or Prevnar 13™ | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following any of the first 3 doses of V114 or Prevnar 13™, the percentage of adult participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed were arthralgia, fatigue, headache, and myalgia. | Up to 14 days after any of the Day 1, Day 30, or Day 60 vaccinations (V114 or Prevnar 13™) | 
| Pediatric Participants: Percentage of Participants With a Solicited Systemic Adverse Event Following Any of the First 3 Doses With V114 or Prevnar 13™ | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following any of the first 3 doses of V114 or Prevnar 13™, the percentage of pediatric participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed were arthralgia, fatigue, headache, myalgia, and hives or welts. | Up to 14 days after any of the Day 1, Day 30, or Day 60 vaccinations (V114 or Prevnar 13™) | 
| Percentage of Participants With a Vaccine-related Serious Adverse Event Up to Month 12 After Allogeneic HSCT | A serious adverse event (SAE) is an AE that is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. The percentage of participants with a vaccine-related SAE following dose 1 (with either V114 or Prevnar 13™) was reported. Vaccine-related SAEs were counted starting after vaccine dose 1 up to 12 months post-HSCT, which could be up to 9 months post-vaccine dose 1. | Up to 9 months | 
| Geometric Mean Concentration (GMC) of Serotype-specific Immunoglobulin G (IgG) at 30 Days Following Dose 3 With V114 or Prevnar 13™ (Day 90) | The GMC of serotype-specific IgG for the serotypes contained in V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. | Day 90 (30 days after the Day 60 vaccinations with V114 or Prevnar 13™) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult Participants: Percentage of Participants With a Solicited Injection-site Adverse Event Following Vaccination With PNEUMOVAX™23 | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following a single dose vaccination with PNEUMOVAX™23, the percentage of adult participants with solicited injection-site AEs was assessed. The solicited injection-site AEs were erythema, pain, and swelling. | Up to 5 days after the PNEUMOVAX™23 vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Pediatric Participants: Percentage of Participants With a Solicited Injection-site Adverse Event Following Vaccination With PNEUMOVAX™23 | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following single dose vaccination with PNEUMOVAX™23, the percentage of pediatric participants with solicited injection-site AEs was assessed. The solicited injection-site AEs assessed were induration, pain, swelling, and erythema. | Up to 14 days after the PNEUMOVAX™23 vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Adult Participants: Percentage of Participants With a Solicited Systemic Adverse Event Following Vaccination With PNEUMOVAX™23 | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following a single dose vaccination with PNEUMOVAX™23, the percentage of adult participants with solicited systemic AEs was assessed. The solicited systemic AEs were arthralgia, fatigue, headache, and myalgia. | Up to 14 days after the PNEUMOVAX™23 vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Pediatric Participants: Percentage of Participants With a Solicited Systemic Adverse Event Following Vaccination With PNEUMOVAX™23 | An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following a single dose vaccination with PNEUMOVAX™23, the percentage of pediatric participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed were fatigue, headache, myalgia, hives or welts, and arthralgia. | Up to 14 days after the PNEUMOVAX™23 vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Percentage of Participants With a Vaccine-related Serious Adverse Event Following Vaccination With PNEUMOVAX™23 | A SAE is an AE that is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. The percentage of participants with a vaccine-related SAE following a single dose vaccination with PNEUMOVAX™23 was reported. | Up to 1 month after PNEUMOVAX™23 vaccination (12 months after HSCT and approximately 6 to 10 months after Day 1) | 
| Adult Participants With GVHD: Percentage of Participants With a Solicited Injection-site Adverse Event Following Dose 4 With V114 or Prevnar 13™ | This end point applies to adult participants who developed GVHD within 12 months of HSCT and received V114 or Prevnar 13™ as the fourth vaccination. An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following dose 4 with V114 or Prevnar 13™, the percentage of adult participants with solicited injection-site AEs was assessed. The solicited injection-site AEs were erythema, pain, and swelling. | Up to 5 days after the fourth V114 or Prevnar 13™ vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Pediatric Participants With GVHD: Percentage of Participants With a Solicited Injection-site Adverse Event Following Dose 4 With V114 or Prevnar 13™ | This end point applies to pediatric participants who developed GVHD within 12 months of HSCT and received V114 or Prevnar 13™ as the fourth vaccination dose. An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following dose 4 with V114 or Prevnar 13™, the percentage of pediatric participants with solicited injection-site AEs was assessed. The solicited injection-site AE assessed were pain, erythema, swelling, and induration. | Up to 14 days after the fourth V114 or Prevnar 13™ vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Adult Participants With GVHD: Percentage of Participants With a Solicited Systemic Adverse Event Following Dose 4 With V114 or Prevnar 13™ | This end point applies to adult participants who developed GVHD within 12 months of HSCT and received V114 or Prevnar 13™ as the fourth vaccination dose. An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following dose 4 with V114 or Prevnar 13™, the percentage of adult participants with solicited systemic AEs was assessed. The solicited systemic AEs were arthralgia, fatigue, headache, and myalgia. | Up to 14 days after the fourth V114 or Prevnar 13™ vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Pediatric Participants With GVHD: Percentage of Participants With a Solicited Systemic Adverse Event Following Dose 4 With V114 or Prevnar 13™ | This end point applies to pediatric participants who developed GVHD within 12 months of HSCT and received V114 or Prevnar 13™ as the fourth vaccination. An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Following dose 4 with V114 or Prevnar 13™, the percentage of pediatric participants with solicited systemic AEs was assessed. The solicited systemic AEs assessed myalgia, arthralgia, headache, fatigue, and hives or welts. | Up to 14 days after the fourth V114 or Prevnar 13™ vaccination (12 months after HSCT and approximately 6 to 9 months after Day 1) | 
| Participants With GVHD: Percentage of Participants With a Vaccine-related Serious Adverse Event Following Dose 4 With V114 or Prevnar 13™ | This end point applies to participants who developed GVHD within 12 months of HSCT and received V114 or Prevnar 13™ as vaccine dose 4. An SAE is an AE that is life-threatening, requires or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is another important medical event deemed such by medical or scientific judgment. The percentage of participants with a vaccine-related SAE following dose 4 with V114 or Prevnar 13™ through completion of study was reported. | Up to 6 months after the fourth V114 or Prevnar 13™ vaccination (12 months after HSCT and approximately 6 to 15 months after Day 1) | 
| Geometric Mean Titer of Serotype-specific Opsonophagocytic Activity at 30 Days Following Dose 3 With V114 or Prevnar 13™ (Day 90) | The GMT of serotype-specific OPA for the serotypes contained in V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using a multiplexed opsonophagocytic assay. | Up to Day 90 (30 days after the Day 60 vaccinations with V114 or Prevnar 13™) | 
| Percentage of Participants With Geometric Mean Fold Rises (GMFR) ≥4 in Serotype-specific IgG at 30 Days Following Dose 3 With V114 or Prevnar 13™ (Day 90) | The GMFR of serotype-specific IgG for the serotypes contained in V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using an electrochemiluminescence assay. | Day 1 (Baseline) and Day 90 (30 days after the Day 60 vaccinations with V114 or Prevnar 13™) | 
| Percentage of Participants With GMFR ≥4 in Serotype-specific OPA at 30 Days Following Dose 3 With V114 or Prevnar 13™ (Day 90) | Activity for the 15 serotypes contained in V114 vaccine were determined using a Multiplex Opsonophagocytic Assay. The GMFR of serotype-specific OPA for the serotypes contained in V114 (13 serotypes shared with Prevnar 13™ and 2 serotypes unique to V114) was determined using multiplexed opsonophagocytic assay. | Time Frame: Day 1 (Baseline) and Day 90 (30 days after the Day 60 vaccinations with V114 or Prevnar 13™) |