PD-L1 Peptide Vaccination in High Risk Smoldering Multiple Myeloma

Smoldering Multiple Myeloma Clinical Trial

Official title:

Phase IIa Trial of PD-L1 Peptide Vaccination as Monotherapy in High Risk Smoldering Multiple Myeloma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03850522
• Other study ID #: MY18H2
• Secondary ID: 2018-003990-93
• Status: Terminated
• Phase: Phase 2
• Start date: February 18, 2019
• Est. completion date: March 10, 2021

Study information

• Verified date: April 2022
• Source: Herlev Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is evaluating a new vaccine against PD-L1 as a possible treatment for high-risk smoldering multiple myeloma.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: March 10, 2021
• Est. primary completion date: March 10, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Smoldering Multiple Myeloma

Intervention

Biological:
• PD-L1 peptide
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.

Locations

Country	Name	City	State
Denmark	Department of Hematology, Universityhospital Herlev and Gentofte	Herlev

Sponsors (2)

Lead Sponsor	Collaborator
Lene Meldgaard Knudsen	IO Biotech

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life (QoL)	measured by change in European Organization for Research and Treatment of Cancer (EORTC) QLQ-30.	Baseline and up to two weeks after last vaccination
Other	Quality of Life (QoL)	measured by change in EuroQoL 5D-5-Level (EQ-5D-5L).	Baseline and up to two weeks after last vaccination
Other	Quality of Life (QoL)	measured by change in and Hospital Anxiety and Depression Scale (HADS).	Baseline and up to two weeks after last vaccination
Primary	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.	Planned analysis cut-off per patient: two weeks after last vaccination.
Secondary	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.	Samples taken before, during and two weeks after last vaccination.
Secondary	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.	Planned analysis cut-off per patient: two weeks after last vaccination
Secondary	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.	Planned analysis 2 years and 5 years post initiation of therapy.
Secondary	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)	Planned analysis 2 years and 5 years post initiation of therapy.
Secondary	Overall survival (OS)	OS from diagnosis is defined as the time from diagnosis to the death of the patient.	Planned analysis 2 years and 5 years post initiation of therapy.