The TG01 Study With TG01/QS-21 Vaccine in Patients With High-risk Smouldering Multiple Myeloma and Multiple Myeloma

Study Overview
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Brief Summary
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The goal of this clinical trial is to test the safety, tolerability, and efficacy of TG01 vaccination in patients with KRAS or NRAS mutation on codon 12/13 mutation who has multiple myeloma or high-risk smoldering multiple myeloma. The main question it aims to answer are: Is TG01/QS-21 vaccination safe and tolerable for this patient group? Is TG01/QS-21 vaccination treatment efficient in this group in terms of increased overall response rate, overall survival rate, progression-free survival, and time til next treatment? Is there an immunological response to the vaccine? Participants will be given TG01/QS-21 vaccination treatment. Treatment consists of 12 doses of TG01/QS-21 vaccine given every two weeks in the first 12 weeks, followed by every eight weeks until week 52.

Official Title
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A Phase 1/Phase 2 Study to Investigate Safety, Tolerability and Efficacy With TG01/QS-21 Vaccine Administration in Patients With Confirmed KRAS or NRAS Codon 12/13 Mutation and High-risk Smoldering Multiple Myeloma or Multiple Myeloma and Evidence of Measurable Disease ≥ 1 Line of Treatment

Conditions
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Multiple Myeloma, Smoldering Multiple Myeloma

Intervention / Treatment
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* Biological: TG01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years of age RAS mutation (KRAS/NRAS codon 12/13 mutation) detected on archival or fresh bone marrow material with VariantPlex Myeloid Panel Confirmed diagnosis of high-risk smoldering multiple myeloma (SMM) according to IMWG criteria (30) and high-risk criteria as listed up below OR confirmed diagnosis of multiple myeloma (MM) according to IMWG criteria and measurable disease following ≥ 1 line of treatment In patients with high-risk SMM at least 2 of 3 following abnormalities, based on laboratory data obtained at screening must be fulfilled: Serum M-protein >20 g/L. Serum involved/uninvolved FLC ratio >20. BMPC >20%. OR presence of ≥10% BMPC and at least one of the following based on laboratory data obtained at screening: Serum M-protein ≥30 g/L (If IgA, IgA ≥20g/L) Serum involved/uninvolved FLC ratio ≥8 (but <100) Abnormal PC immunophenotype (≥95% of BMPCs are clonal) and reduction of ≥1uninvolved Ig isotype (Only IgG, IgA and IgM will be considered) Progressive increase in Serum M-protein level (evolving type of SMM) defined as an increase of Serum M-protein ≥10% in the last 12 months before enrolment in the study. This increase must be consistent from one to another sample (i.e., no decrease observed between 2 increased Serum M-protein values) Both high-risk SMM and MM patients must have evidence of measurable disease in accordance with IMWG criteria If patient with MM was eligible for ASCT, ASCT must have been performed, and patients cannot be enrolled until 3 months after ASCT Patient should not be expected to require immediate, subsequent line of treatment for at least 2 months Patient has not had reduction of clonal plasma cell markers for last two cycles (last two months if off treatment). If a patient had no reduction during the last two cycles of induction before ASCT, the patient can be enrolled, provided 3 months after ASCT Following ASCT, the patient cannot be enrolled without having tried lenalidomide maintenance given at standard doses for at least two cycles, if the clonal markers had a reduction during the last 2 cycles of induction treatment. Lenalidomide will be stopped when entering the study ECOG performance status 0-1 Female patients of child-bearing potential (FCBP) must have negative serum pregnancy test at Screening and agree to use a highly effective method of contraception during treatment and for 3 months following last dose of drug. Male patients must use an effective barrier method of contraception during treatment and for 3 months following the last dose if sexually active with a FCBP. Ability to provide written informed consent and can understand and comply with the requirements of the study Exclusion Criteria: Pregnant or lactating women or women without a pregnancy test at baseline (postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential) Medical conditions such as but not limited to: Any uncontrolled infection Uncontrolled cardiac failure classification III or IV (NYHA) Uncontrolled systemic and gastro-intestinal inflammatory conditions History of adverse reactions to vaccines Active malignancy with worse prognosis than multiple myeloma Likely to require treatment intervention for multiple myeloma within two months of start of treatment with TG01/QS-21 Known history of positive tests for HIV/AIDS, hepatitis B or C Planned to receive yellow fever or other live (attenuated) vaccines during the course of study Known hypersensitivity to QS-21. Only participants who are able to consent will be included in the study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TG01<br>TG01 is a sterile lyophilizate consisting of a mixture of seven peptides. The finished product is a white powder for injection, consisting only of the active substances containing 2.1 mg of peptides (individual peptides comprising 0.3 mg each). The lyophilizate is to be reconstituted with QS-21 for injection before use. QS-21 is a naturally occurring saponin molecule purified from the South American tree Quillaja saponaria Molina. QS-21 Solution is supplied in a 2 mL CZ resin vial as a sterile, solution in PBS (phosphate buffered saline) at a concentration of 0.5 mg/mL QS-21 (500 mcg/mL) with each vial containing 0.7 mL intended single use only. The vaccine will be given subcutaneously Treatment consists of 12 doses TG01/QS-21 vaccine given every 2 weeks in the first 12 weeks, followed by every 8 weeks until week 52. TG01 dose 0.7 mg dose and QS-21 50 ug. | Biological: TG01<br>* All participants will receive the same treatment as described under arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with adverse events (AEs) | An Adverse Event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Baseline until 30 days after last dose of study drug, up to approximately 3 years | 
| Percentage of participants discontinuing treatment secondary to treatment-related adverse events | Percentage of participants discontinuing treatment secondary to treatment-related adverse events | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Progression Free Survival (PFS) | defined as the time from study treatment start to disease progression for every patient | Baseline to 11 years | 
| Concentration of TG01-specific T-cell specific cytokine production | The immune response to TG01 will be measured by IFNg/TNFa ELISPOT or FluoroSpot quantifying the TG01 T-cell specific cytokine production. A positive immune response will be defined as a 2-fold higher mean spot number in experimental wells (with vaccine peptides) compared to control wells (medium) | Baseline until end of study, assessed up to 11 years | 
| Overall response rate per patient | The proportion of patients who achieve partial response (PR) or better following at least one dose of study treatment | Baseline to approximately 3 years | 
| Overall Survival (OS) per patient | The OS rate of patients receiving 1 or more study treatments | Baseline until the end of study, assessed up to 11 years | 
| Time to next treatment (TTNT) per patient | defined as the time between the start date of the current treatment line and the start date of the next treatment line | Baseline until the end of study, assessed up to 11 years |