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PD-L1 Peptide Vaccination in High Risk Smoldering Multiple Myeloma

Primary Purpose

Smoldering Multiple Myeloma

Status
Terminated
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
PD-L1 peptide
Sponsored by
Lene Meldgaard Knudsen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Smoldering Multiple Myeloma focused on measuring smoldering, myeloma, vaccination, PD-L1, high-risk

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient has confirmed SMM according to a definition derived from the International Myeloma Working Group (IMWG) definition (International Working Group, 2003)

    1. Serum M-component >30g/L and/or
    2. Urine M-component ≥ 500mg/24 hours and/or
    3. ≥10% clonal plasma cells in bone marrow
    4. and no CRAB criteria or myeloma defining events (see exclusion criteria)
  • High risk of progression to symptomatic multiple myeloma defined by the presence of ≥ 2 of the risk factors below:

    • Bone marrow Plasma Cells (BMPCs) ≥ 20%
    • M-component > 2g/dL
    • FLC ratio > 20
  • Age ≥18 years
  • Performance status ≤ 2 (ECOG-scale)
  • Expected survival > 3 months
  • Sufficient liver function, i.e.

    1. ALAT < 2.5 upper normal limit, i.e. ALAT <112 U/l
    2. Bilirubin < 30 U/l
  • Women agreement to use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 120 days after the last treatment.
  • For men: agreement to use contraceptive measures and agreement to refrain from donating sperm.
  • The accepted contraceptive methods are

    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation. Oral, intravaginal or transdermal.
    • Progestogen-only hormonal contraception associated with inhibition of ovulation. Oral, injectable, implantable.
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomized partner
    • Sexual abstinence

Exclusion Criteria:

  • Non-secretory myeloma
  • Patients fulfilling CRAB criteria:

    i. C: Hypercalcemia,

    1. s-Ca-ion >1,40 mmol/L, attributable to myeloma ii. R: Renal failure

    1. Estimated or measured creatinine clearance <40ml/min, attributable to myeloma
    2. Increased s-creatinine, attributable to myeloma
    3. Decrease in estimated or measured creatinine clearance <35% within a year, attributable to myeloma
    4. Renal biopsy-verified renal changes attributable to myeloma iii. A: Anemia, Hgb < 6,3mmol/L (10g/dl), attributable to myeloma iv. B: Bone lesions on X-ray, CT or PET-CT
  • Evidence of myeloma defining events i. Clonal bone marrow plasma cell percentage ≥ 60% ii. Ratio of involved/uninvolved serum free light chain ratio ≥ 100 iii. >1 focal lesions on MRI studies, if clinically indicated
  • Plasma cell leukemia
  • Signs of amyloidosis
  • Other malignancies in the medical history excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer and patients cured for another malignant disease with no sign of relapse two years after ended treatment.
  • Significant medical condition per investigators judgement e.g. severe Asthma/COPD, poorly regulated heart condition, insulin dependent diabetes mellitus.
  • Acute or chronic viral infection e.g. HIV, hepatitis or tuberculosis
  • Serious known allergies or earlier anaphylactic reactions.
  • Known sensibility towards Montanide ISA-51
  • Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc.
  • Pregnant and breastfeeding women.
  • Fertile women not using secure contraception with a failure rate less than < 1%
  • Patients taking immune suppressive medications incl. corticosteroids and methotrexate at the time of enrollment
  • Psychiatric disorders that per investigator judgment could influence compliance.
  • Treatment with other experimental drugs
  • Concurrent treatment with other anti-cancer drugs.

Sites / Locations

  • Department of Hematology, Universityhospital Herlev and Gentofte

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Vaccination

Arm Description

Vaccination with PD-L1 peptide

Outcomes

Primary Outcome Measures

Overall response rate
Overall response rates (ORR) defined by IMWG criteria as PR+VGPR+CR+sCR during treatment and two weeks after end of treatment per patient.

Secondary Outcome Measures

Immunogenicity of the PD-L1 vaccine
Blood, skin biopsies and bone marrow samples will be assessed with ELISPOT assays for levels of immune response to the vaccine.
Incidence of Treatment Emergent Adverse Events
Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.
Progression-free survival (PFS)
PFS from diagnosis is defined as the time from diagnosis to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free. This will be compared with published progression rates.
Time to progression (TTP)
Time from diagnosis of SMM to progression to symptomatic myeloma compared to historical controls. Progression is defined as biochemical or diagnostic progression in accordance with the 2014 IMWG criteria for diagnosis of multiple myeloma which includes the classic CRAB-criteria as well as: Clonal bone marrow plasma cell percentage ≥ 60%, Free light chain ratio ≥ 100 (Involved FLC level must be ≥ 100mg/L),> 1 focal lesion on MRI studies (at least 5 mm in size)
Overall survival (OS)
OS from diagnosis is defined as the time from diagnosis to the death of the patient.

Full Information

First Posted
February 19, 2019
Last Updated
April 8, 2022
Sponsor
Lene Meldgaard Knudsen
Collaborators
IO Biotech
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1. Study Identification

Unique Protocol Identification Number
NCT03850522
Brief Title
PD-L1 Peptide Vaccination in High Risk Smoldering Multiple Myeloma
Official Title
Phase IIa Trial of PD-L1 Peptide Vaccination as Monotherapy in High Risk Smoldering Multiple Myeloma
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Terminated
Why Stopped
Insufficient recruitment within planned enrolmentperiod.
Study Start Date
February 18, 2019 (Actual)
Primary Completion Date
March 10, 2021 (Actual)
Study Completion Date
March 10, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lene Meldgaard Knudsen
Collaborators
IO Biotech

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This study is evaluating a new vaccine against PD-L1 as a possible treatment for high-risk smoldering multiple myeloma.
Detailed Description
Smoldering multiple myeloma is an asymptomatic disorder with an annual risk of 10% of progression to the incurable cancer multiple myeloma. While many patients live for many years without progression, high risk patients have a median risk of progression of 29 months. No therapy has been approved for this indication. New treatments with limited adverse events are in high demand for this unmet medical need. An effective peptide vaccine would represent an ideal candidate, since vaccines generally have very low levels of side effects. This study will explore if vaccination against the immune checkpoint molecule PD-L1 leads to responses in patients with high risk smoldering myeloma. PD-L1 is thought to play a role in the rate of progression from smoldering myeloma to symptomatic myeloma. Targeting this pathway with little risk of adverse events would potentially prevent or delay progression to symptomatic myeloma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Smoldering Multiple Myeloma
Keywords
smoldering, myeloma, vaccination, PD-L1, high-risk

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vaccination
Arm Type
Experimental
Arm Description
Vaccination with PD-L1 peptide
Intervention Type
Biological
Intervention Name(s)
PD-L1 peptide
Other Intervention Name(s)
IO103
Intervention Description
PD-L1 peptide (100 micrograms) emulsified with the adjuvant Montanide ISA-51 given subcutaneously 10 times every second week over the course of 26 weeks including a five-week break.
Primary Outcome Measure Information:
Title
Overall response rate
Description
Overall response rates (ORR) defined by IMWG criteria as PR+VGPR+CR+sCR during treatment and two weeks after end of treatment per patient.
Time Frame
Planned analysis cut-off per patient: two weeks after last vaccination.
Secondary Outcome Measure Information:
Title
Immunogenicity of the PD-L1 vaccine
Description
Blood, skin biopsies and bone marrow samples will be assessed with ELISPOT assays for levels of immune response to the vaccine.
Time Frame
Samples taken before, during and two weeks after last vaccination.
Title
Incidence of Treatment Emergent Adverse Events
Description
Safety analysis will be conducted using the Safety Population defined as any patient receiving one dose of study treatment. For toxicity reporting, all adverse events and laboratory abnormalities will be graded and analyzed using CTCAE version 4 as appropriate.
Time Frame
Planned analysis cut-off per patient: two weeks after last vaccination
Title
Progression-free survival (PFS)
Description
PFS from diagnosis is defined as the time from diagnosis to the disease progression or death from any cause. Patients who have not progressed or died are censored at the date last known progression-free. This will be compared with published progression rates.
Time Frame
Planned analysis 2 years and 5 years post initiation of therapy.
Title
Time to progression (TTP)
Description
Time from diagnosis of SMM to progression to symptomatic myeloma compared to historical controls. Progression is defined as biochemical or diagnostic progression in accordance with the 2014 IMWG criteria for diagnosis of multiple myeloma which includes the classic CRAB-criteria as well as: Clonal bone marrow plasma cell percentage ≥ 60%, Free light chain ratio ≥ 100 (Involved FLC level must be ≥ 100mg/L),> 1 focal lesion on MRI studies (at least 5 mm in size)
Time Frame
Planned analysis 2 years and 5 years post initiation of therapy.
Title
Overall survival (OS)
Description
OS from diagnosis is defined as the time from diagnosis to the death of the patient.
Time Frame
Planned analysis 2 years and 5 years post initiation of therapy.
Other Pre-specified Outcome Measures:
Title
Quality of Life (QoL)
Description
measured by change in European Organization for Research and Treatment of Cancer (EORTC) QLQ-30.
Time Frame
Baseline and up to two weeks after last vaccination
Title
Quality of Life (QoL)
Description
measured by change in EuroQoL 5D-5-Level (EQ-5D-5L).
Time Frame
Baseline and up to two weeks after last vaccination
Title
Quality of Life (QoL)
Description
measured by change in and Hospital Anxiety and Depression Scale (HADS).
Time Frame
Baseline and up to two weeks after last vaccination

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient has confirmed SMM according to a definition derived from the International Myeloma Working Group (IMWG) definition (International Working Group, 2003) Serum M-component >30g/L and/or Urine M-component ≥ 500mg/24 hours and/or ≥10% clonal plasma cells in bone marrow and no CRAB criteria or myeloma defining events (see exclusion criteria) High risk of progression to symptomatic multiple myeloma defined by the presence of ≥ 2 of the risk factors below: Bone marrow Plasma Cells (BMPCs) ≥ 20% M-component > 2g/dL FLC ratio > 20 Age ≥18 years Performance status ≤ 2 (ECOG-scale) Expected survival > 3 months Sufficient liver function, i.e. ALAT < 2.5 upper normal limit, i.e. ALAT <112 U/l Bilirubin < 30 U/l Women agreement to use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 120 days after the last treatment. For men: agreement to use contraceptive measures and agreement to refrain from donating sperm. The accepted contraceptive methods are Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation. Oral, intravaginal or transdermal. Progestogen-only hormonal contraception associated with inhibition of ovulation. Oral, injectable, implantable. Intrauterine device (IUD) Intrauterine hormone-releasing system (IUS) Bilateral tubal occlusion Vasectomized partner Sexual abstinence Exclusion Criteria: Non-secretory myeloma Patients fulfilling CRAB criteria: i. C: Hypercalcemia, 1. s-Ca-ion >1,40 mmol/L, attributable to myeloma ii. R: Renal failure Estimated or measured creatinine clearance <40ml/min, attributable to myeloma Increased s-creatinine, attributable to myeloma Decrease in estimated or measured creatinine clearance <35% within a year, attributable to myeloma Renal biopsy-verified renal changes attributable to myeloma iii. A: Anemia, Hgb < 6,3mmol/L (10g/dl), attributable to myeloma iv. B: Bone lesions on X-ray, CT or PET-CT Evidence of myeloma defining events i. Clonal bone marrow plasma cell percentage ≥ 60% ii. Ratio of involved/uninvolved serum free light chain ratio ≥ 100 iii. >1 focal lesions on MRI studies, if clinically indicated Plasma cell leukemia Signs of amyloidosis Other malignancies in the medical history excluding basal cell carcinoma of the skin, squamous cell carcinoma of the skin or in situ cervical cancer and patients cured for another malignant disease with no sign of relapse two years after ended treatment. Significant medical condition per investigators judgement e.g. severe Asthma/COPD, poorly regulated heart condition, insulin dependent diabetes mellitus. Acute or chronic viral infection e.g. HIV, hepatitis or tuberculosis Serious known allergies or earlier anaphylactic reactions. Known sensibility towards Montanide ISA-51 Any active autoimmune diseases e.g. autoimmune neutropenia, thrombocytopenia or hemolytic anemia, systemic lupus erythematosus, scleroderma, myasthenia gravis, autoimmune glomerulonephritis, autoimmune adrenal deficiency, autoimmune thyroiditis etc. Pregnant and breastfeeding women. Fertile women not using secure contraception with a failure rate less than < 1% Patients taking immune suppressive medications incl. corticosteroids and methotrexate at the time of enrollment Psychiatric disorders that per investigator judgment could influence compliance. Treatment with other experimental drugs Concurrent treatment with other anti-cancer drugs.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolai Jørgensen, MD
Organizational Affiliation
Department of Hematology
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Hematology, Universityhospital Herlev and Gentofte
City
Herlev
ZIP/Postal Code
2730
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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PD-L1 Peptide Vaccination in High Risk Smoldering Multiple Myeloma

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