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

Pneumococcal Infections Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03565900
• Other study ID #: V114-022
• Secondary ID: V114-0222018-000
• Status: Completed
• Phase: Phase 3
• Start date: September 12, 2018
• Est. completion date: November 4, 2021

Study information

• Verified date: July 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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]).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 277
• Est. completion date: November 4, 2021
• Est. primary completion date: November 4, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Pneumococcal Infections

Intervention

Biological:
• V114
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.
• Prevnar 13™
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
• PNEUMOVAX™23
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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital ( Site 0040)	Adelaide	South Australia
Australia	Austin Health-Austin Hospital ( Site 0038)	Heidelberg	Victoria
Australia	The Alfred Hospital ( Site 0037)	Melbourne	Victoria
Australia	Royal Melbourne Hospital ( Site 0039)	Parkville	Victoria
Australia	St. Vincent's Hospital ( Site 0041)	Sydney	New South Wales
Australia	The Children s Hospital at Westmead ( Site 0191)	Westmead	New South Wales
Belgium	AZ Sint Jan Brugge-Oostende ( Site 0118)	Brugge	West-Vlaanderen
Belgium	Cliniques Universitaires Saint-Luc ( Site 0122)	Brussels	Bruxelles-Capitale, Region De
Belgium	UZ Leuven ( Site 0119)	Leuven	Vlaams-Brabant
Belgium	Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman ( Site 0121)	Liège
Belgium	AZ Delta ( Site 0120)	Roeselare	West-Vlaanderen
Brazil	Santa Casa de Misericordia de Belo Horizonte ( Site 0050)	Belo Horizonte	Minas Gerais
Brazil	Instituto de Cancer e Transplante de Curitiba ICTR ( Site 0051)	Curitiba	Paraná
Brazil	Hospital Sao Rafael ( Site 0049)	Salvador	Bahia
Canada	Nova Scotia Health Authority QEII-HSC ( Site 0033)	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre ( Site 0032)	Hamilton	Ontario
Canada	CIUSSS de l Est de L Ile de Montreal - Hopital Maisonneuve-Rosemont ( Site 0031)	Montreal	Quebec
Colombia	Centro Medico Imbanaco de Cali S.A ( Site 0075)	Cali	Valle Del Cauca
Colombia	Fundacion Valle del Lili ( Site 0073)	Cali	Valle Del Cauca
Colombia	Hospital Pablo Tobon Uribe ( Site 0077)	Medellin	Antioquia
France	Hopital Jean Minjoz Besancon ( Site 0085)	Besancon	Doubs
France	CHU Henri Mondor ( Site 0081)	Creteil	Val-de-Marne
France	CHU de Grenoble Hopital Nord ( Site 0083)	La Tronche	Isere
France	CHRU de Lille - Hopital Claude Huriez ( Site 0090)	Lille	Nord
France	CHU de Nice ( Site 0084)	Nice	Alpes-Maritimes
France	Hopital Saint-Antoine ( Site 0089)	Paris
Germany	Universitaetsklinikum Duesseldorf ( Site 0107)	Duesseldorf	Nordrhein-Westfalen
Germany	Universitaetsklinikum Koeln ( Site 0105)	Koeln	Nordrhein-Westfalen
Germany	Universitaetsmedizin Mainz ( Site 0106)	Mainz	Rheinland-Pfalz
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0058)	Ciudad de Mexico
Mexico	Instituto Nacional de Pediatria ( Site 0062)	Ciudad de Mexico
Mexico	Hospital Espanol ( Site 0059)	Mexico
Mexico	Instituto Nacional de Cancerologia. ( Site 0060)	Mexico
Mexico	Hospital Infantil de Mexico Federico Gomez ( Site 0061)	Mexico City
Mexico	Hospital Universitario Dr. Jose Eleuterio Gonzalez ( Site 0187)	Monterrey	Nuevo Leon
Mexico	Servicio de hematologia Universidad Autonoma de Nuevo Leon ( Site 0057)	Monterrey	Nuevo Leon
Sweden	Sahlgrenska Universitetssjukhuset ( Site 0145)	Goteborg	Vastra Gotalands Lan [se-14]
Sweden	Karolinska Universitetssjukhuset ( Site 0143)	Stockholm	Stockholms Lan [se-01]
Sweden	Akademiska Sjukhuset ( Site 0144)	Uppsala	Uppsala Lan [se-03]
United States	Children's Hospital Colorado ( Site 0166)	Aurora	Colorado
United States	Johns Hopkins - University ( Site 0023)	Baltimore	Maryland
United States	Montefiore Einstein Center ( Site 0164)	Bronx	New York
United States	University of Chicago ( Site 0016)	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center ( Site 0010)	Cincinnati	Ohio
United States	Cleveland Clinic Foundation ( Site 0168)	Cleveland	Ohio
United States	University of Florida ( Site 0011)	Gainesville	Florida
United States	Baylor College of Medicine - Texas Children's Hospital ( Site 0165)	Houston	Texas
United States	Indiana Blood and Marrow Transplantation ( Site 0001)	Indianapolis	Indiana
United States	Children's Mercy Hospital ( Site 0167)	Kansas City	Missouri
United States	University of Kansas Medical Center ( Site 0007)	Kansas City	Kansas
United States	Stanford Health Care ( Site 0005)	Palo Alto	California
United States	Oregon Health & Science University ( Site 0018)	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Colombia,  France,  Germany,  Mexico,  Sweden, 

References & Publications (1)

Wilck M, Cornely OA, Cordonnier C, Velez JD, Ljungman P, Maertens J, Selleslag D, Mullane KM, Nabhan S, Chen Q, Dagan R, Richmond P, Daus C, Geddie K, Tamms G, Sterling T, Patel SM, Shekar T, Musey L, Buchwald UK; V114-022 (PNEU-STEM) study group. A phase — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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™)
Primary	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™)
Primary	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™)
Primary	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™)
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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™)
Secondary	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™)
Secondary	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™)