ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622001313729

Ethics application status

Approved

Date submitted

30/08/2022

Date registered

11/10/2022

Date last updated

23/02/2024

Date data sharing statement initially provided

11/10/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

ALLG MM26/D1: Novel Combinations for Orphan Myeloma: The NORM Platform study: Treatment Specific Appendix - Selinexor, Pomalidomide, Dexamethasone (SPd)

Scientific title

ALLG MM26/D1: Novel Combinations for Orphan Myeloma: The NORM Platform study: Treatment Specific Appendix: Selinexor, Pomalidomide, Dexamethasone (SPd)

Secondary ID [1]

Nil known.

Universal Trial Number (UTN)

Trial acronym

NORM:SPd

Linked study record

This study is the first domain of the MM26 NORM platform trial (Master Protocol registered under ACTRN12622001308785).

Health condition

Health condition(s) or problem(s) studied:

Relapsed/ Refractory Multiple Myeloma

Condition category

Condition code

Cancer

Myeloma

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

MM26/D1 is domain 1 of the MM26 NORM Platform trial. This domain will determine the safety and efficacy of Selinexor, Pomalidomide and Dexamethasone in treating patients who have had at least one relapse or refractory multiple myeloma. Participants meeting inclusion for MM26 Master Protocol in Strata A (renal impairment), B (non-measurable disease), C (extramedullary plasmacytoma), or D (CNS myeloma) will be considered for Domain 1, after undergoing separate screening procedures

For participants with renal impairment (Strata A) the study will be conducted in two stages.
Stage 1: A safety run-in stage will confirm the planned optimal dose schedule for these participants. Up to 10 participants will be enrolled in a lead-in safety phase and monitored by the Trial Monitoring Committee (TMC) for treatment related toxicities.
If the initial dose level of Pomalidomide and Selinexor is deemed intolerable, other dose levels will be explored. Decisions to escalate or de-escalate the dose and the identification of the optimal dose will be guided by use of a dual-criteria Bayesian proof-of-concept approach.
If more than 3 of the first 10 evaluable participants have grade 4 related non-haematological toxicity, then the causative agent (pomalidomide or Selinexor) will be determined by the TMC, and a dose reduction instituted as per dose levels described below.
Each treatment cycle will be 28 days for the first two cycles only.
The dose de-escalation schedule for Strata A is as follows:
Level 1 (starting dose):
Pomalidomide 4mg (oral) – Daily for days 1 to 21
Selinexor 60mg (oral) - weekly
Level 2:
Pomalidomide 3mg (oral) Daily for days 1 to 21
Selinexor 40mg (oral) - weekly
Level 3:
Pomalidomide 2mg (oral) Daily for days 1 to 21.
Selinexor 20mg (oral) - weekly

Stage 2: Provided that no more than 3 participants in the first 10 evaluable participants develop grade 4 treatment-related toxicities, the stratum will proceed to the expansion phase. Participants proceeding to the expansion phase will continue with treatment at the recommended dose determined in the lead-in phase. Expansion phase continues until the participant withdraws from disease progression or unacceptable toxicity.

For all other participants from Strata B (Non-measurable disease), Strata C (Extramedullary plasmacytomas) and Strata D (CNS involvement) the following study treatment will be assigned in a 28-day cycle:

Selinexor 60mg (oral) weekly
Pomalidomide 4mg on days 1 to 21 (oral)
Dexamethasone 40mg (oral) weekly (20mg if greater than 75 years old).

All participants enrolled to Domain 1 will continue study medication unless they develop disease progression, unacceptable treatment related toxicities, withdraw consent or are loss to follow-up.

Compliance will be monitored via drug accountability exercises completed by the participating site and the sponsor.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

To determine the efficacy of treatment with Selinexor, Pomalidomide, Dexamethasone (SPd) in each of four strata of orphan myeloma in the first 4 cycles of therapy.

Stratum A: refers to patients with renal impairment (creatinine clearance of less than 30mls per minute)

Timepoint [1]

Achievement of a partial response (PR) or better at any time up to the end of cycle 4.

Response rates are defined by the International Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment in multiple myeloma. The following response rates are considered to be PR or better:

PR is defined in IMWG criteria as greater than or equal to 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by greater than or equal to 90% or to less than 200 mg per 24 hours;
- If the serum and urine M-protein are unmeasurable, a greater than or equal to 50% decrease in the difference between involved and uninvolved Free Light Chain (FLC) levels is required in place of the M-protein criteria;
- If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, greater than or equal to 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was greater than or equal to 30%. In addition to these criteria, if present at baseline, a greater than or equal to 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Very good partial response (VGPR) is defined in IMWG criteria as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 h.

Complete response (CR) is defined in IMWG criteria as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5% plasma cells in bone marrow aspirates.

Stringent complete response (sCR.) is defined in IMWG criteria as a complete response below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (kappa/lambda ratio less than or equal to 4:1 or greater than or equal to 1:2 for kappa and lambda patients, respectively, after counting greater than 100 plasma cells).

Primary outcome [2]

To determine the efficacy of treatment with Selinexor, Pomalidomide, Dexamethasone (SPd) in each of four strata of orphan myeloma in the first 4 cycles of therapy.

Stratum B: refers to patients with non-measurable disease (paraprotein less than 10g/dl).

Timepoint [2]

Achievement of a partial response (PR) or better at any time up to the end of cycle 4.

Response rates are defined by the International Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment in multiple myeloma. The following response rates are considered to be PR or better:

PR is defined in IMWG criteria as greater than or equal to 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by greater than or equal to 90 %or to less than 200 mg per 24 hours;
- If the serum and urine M-protein are unmeasurable, a greater than or equal to 50% decrease in the difference between involved and uninvolved Free Light Chain (FLC) levels is required in place of the M-protein criteria;
- If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, greater than or equal to 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was greater than or equal to 30%. In addition to these criteria, if present at baseline, a greater than or equal to 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Very good partial response (VGPR) is defined in IMWG criteria as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 h.

Complete response (CR) is defined in IMWG criteria as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5% plasma cells in bone marrow aspirates.

Stringent complete response (sCR.) is defined in IMWG criteria as a complete response below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (kappa/lambda ratio less than or equal to 4:1 or greater than or equal to 1:2 for kappa and lambda patients, respectively, after counting greater than 100 plasma cells).

Primary outcome [3]

To determine the efficacy of treatment with Selinexor, Pomalidomide, Dexamethasone (SPd) in each of four strata of orphan myeloma in the first 4 cycles of therapy.

Stratum C: Refers to patients with extramedullary plasmacytomas.

Timepoint [3]

Achievement of a partial response (PR) or better at any time up to the end of cycle 4.

Response rates are defined by the International Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment in multiple myeloma. The following response rates are considered to be PR or better:

PR is defined in IMWG criteria as greater than or equal to 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by greater than or equal to 90 %or to less than 200 mg per 24 hours;
- If the serum and urine M-protein are unmeasurable, a greater than or equal to 50% decrease in the difference between involved and uninvolved Free Light Chain (FLC) levels is required in place of the M-protein criteria;
- If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, greater than or equal to 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was greater than or equal to 30%. In addition to these criteria, if present at baseline, a greater than or equal to 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Very good partial response (VGPR) is defined in IMWG criteria as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 h.

Complete response (CR) is defined in IMWG criteria as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5% plasma cells in bone marrow aspirates.

Stringent complete response (sCR.) is defined in IMWG criteria as a complete response below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (kappa/lambda ratio less than or equal to 4:1 or greater than or equal to 1:2 for kappa and lambda patients, respectively, after counting greater than 100 plasma cells).

For Strata C (extramedullary plasmacytomas) the following also applies:
- In patients with BM plasma cell percentage greater than 30% and no extramedullary plasmacytomas: use IMWG criteria
- In patients with BM plasma cell percentage greater than 30% and extramedullary plasmacytomas: use IMWG criteria to assess both bone marrow response and response of extramedullary plasmacytomas.
- For patients with BM plasma cell percentage less than 30% and extramedullary plasmacytomas: use IMWG criteria for assessment of extramedullary
plasmacytomas.
- For patients with BM plasma cell percentage less than 30% and no extramedullary plasmacytomas: use PET assessment. Partial response defined as a partial metabolic response.

Secondary outcome [1]

Please note this is a Primary Outcome [4]:

To determine the efficacy of treatment with Selinexor, Pomalidomide, Dexamethasone (SPd) in each of four strata of orphan myeloma in the first 4 cycles of therapy.

Stratum D: Refers to patients with central nervous system involvement.

Timepoint [1]

Achievement of a partial response (PR) or better at any time up to the end of cycle 4.

Response rates are defined by the International Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment in multiple myeloma. The following response rates are considered to be PR or better:

PR is defined in IMWG criteria as greater than or equal to 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by greater than or equal to 90 %or to less than 200 mg per 24 hours;
- If the serum and urine M-protein are unmeasurable, a greater than or equal to 50% decrease in the difference between involved and uninvolved Free Light Chain (FLC) levels is required in place of the M-protein criteria;
- If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, greater than or equal to 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was greater than or equal to 30%. In addition to these criteria, if present at baseline, a greater than or equal to 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Very good partial response (VGPR) is defined in IMWG criteria as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 h.

Complete response (CR) is defined in IMWG criteria as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5% plasma cells in bone marrow aspirates.

Stringent complete response (sCR.) is defined in IMWG criteria as a complete response below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (kappa/lambda ratio less than or equal to 4:1 or greater than or equal to 1:2 for kappa and lambda patients, respectively, after counting greater than 100 plasma cells).

For stratum D (CNS myeloma), the following additional criteria must be met:
(i) no new sites of disease,
(ii) 50% decrease in the contrast-enhancing lesion seen on MRI compared with baseline, and
(iii) a decrease in the vitreous cell count or retinal/optic nerve cellular infiltrate. CSF cytology may continue to show persistent malignant or suspicious cells.

Secondary outcome [2]

To determine the efficacy of a specified novel agent in each of four strata of orphan myeloma at any time on protocol-specified therapy.

Timepoint [2]

Best response (IMWG defined response) at any time on protocol-specified therapy with the novel agent. Response assessments are to be completed on or before the last date of protocol-specified therapy except in the case of PET/CT, CT and MRI scans which can be completed up to 2 weeks after the end of protocol therapy. These assessments can be carried out within 1 week of the end cycle 4, 8, 12, 16 and every 4 cycles until EOT. Patients reach EOT when study treatment is discontinued due to experiencing either unacceptable toxicity, or disease progression.

Response rates are defined by the International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The following response rates are considered to be PR or better:

PR is defined in IMWG criteria as greater than or equal to 50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by greater than or equal to 90% or to less than 200 mg per 24 h;
If the serum and urine M-protein are unmeasurable, a greater than or equal to 50% decrease in the difference between involved and uninvolved Free Light Chain (FLC) levels is required in place of the M-protein criteria;
If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, greater than or equal to 50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was greater than or equal to 30%. In addition to these criteria, if present at baseline, a greater than or equal to 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required

Very good partial response (VGPR) is defined in IMWG criteria as serum and urine M-protein detectable by immunofixation but not on electrophoresis or greater than or equal to 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 h.

Complete response (CR) is defined in IMWG criteria as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and less than 5% plasma cells in bone marrow aspirates.

Stringent complete response (sCR.) is defined in IMWG criteria as a complete response below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (kappa/lambda ratio less than or equal to 4:1 or greater than or equal to 1:2 for kappa and lambda patients, respectively, after counting greater than 100 plasma cells).

Secondary outcome [3]

To investigate the kinetics of response to a novel agent in each of four strata of orphan myeloma in the first 12 months.

Timepoint [3]

Response status (Death, Progressive disease (PD), Stable Disease (SD), Morphological Relapse (MR), Partial Response (PR), Very Good Partial Response (VGPR) and Complete Response (CR)) at the end of cycles 2, 4, 6 and 12. Response assessments are to be completed on or before Day 1 of the following cycle except in the case of PET/CT, CT and MRI scans which can be completed up to 2 weeks after the end of the cycle.

Secondary outcome [4]

To determine durability of progression-free response status in patients treated with a specified novel agent in each of four strata of orphan myeloma.

Timepoint [4]

Progression-free survival (PFS): Measured from the date of randomisation (or registration if the domain has a single arm) to the earlier of the date of progression or death from any cause.

Secondary outcome [5]

To determine the survival of patients treated with a specified novel agent in each of four strata of orphan myeloma.

Timepoint [5]

Overall survival (OS): Measured from the date of randomisation (or registration if the domain has a single arm) to the date of progression or death from any cause.

Secondary outcome [6]

To determine durability of event-free status in patients treated with a specified novel agent in each of four strata of orphan myeloma.

Timepoint [6]

Event-free survival (EFS): Measured from the date of commencement of treatment on study (Cycle 1 Day 1) to the earliest date of these events: date off protocol treatment for any reason (except completion of protocol-specified treatment duration) the date of progression or the date of death from any cause. This data will obtained from source medical data e.g. medical records.

Secondary outcome [7]

Safety: To characterize the safety and tolerability of novel agents in each of the four strata of orphan myeloma.

Timepoint [7]

Occurrence of newly occurring or worsening …
Related CTCAEv5 grade 3-5 non-hematologic adverse events (AEs).
Related CTCAE grade 4-5 neutropenia or thrombocytopenia or grade 3-5 febrile neutropenia in each of the first 4 cycles of therapy. For combination therapies, "relatedness" refers to any agent in the combination. Grade is the worst grade recorded in the cycle, AEs will be reported by participants at any time from the date of commencement of treatment on study (Cycle 1 Day 1) until treatment cessation or death from any cause,

Secondary outcome [8]

To assess the effect of therapy with novel agent(s) on the Quality of Life of patients in the four strata of orphan myeloma.

Timepoint [8]

Quality of Life (QoL) measured using EORTC QLQ-C30 and QLQ-MY20 on Day 1 of each cycle and at EOT. Patients reach EOT when study treatment is discontinued due to experiencing either unacceptable toxicity, or disease progression.

Eligibility

Key inclusion criteria

Eligibility criteria specific to Treatment Specific Appendix - Selinexor, Pomalidomide, Dexamethasone (SPd) include:
1.Previous bortezomib therapy and either: failure to achieve at least a partial response (PR) during treatment OR progressive disease (PD) during treatment or within 6 months of discontinuing treatment OR contraindication or experienced an intolerance to treatment with bortezomib AND
2.Previous lenalidomide therapy and either: treatment failure with lenalidomide, as confirmed by progressive disease during treatment within 6 months of discontinuing lenalidomide OR a contraindication or intolerance to treatment with lenalidomide.
3.Must agree to contraceptive requirements

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

See ALLG MM26/NORM: Novel Combinations for Orphan Myeloma: The NORM platform study Master Protocol for eligibility criteria relevant to all domain protocols.

Exclusion criteria specific to Treatment Specific Appendix - Selinexor, Pomalidomide, Dexamethasone (SPd) include:
1.Previous treatment with pomalidomide or Selinexor
2.Contraindication to pomalidomide, Selinexor or dexamethasone
3.Active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of trial treatments.

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other

Other design features

This study will enrol participants into different strata depending on their disease characteristics:
• Stratum A: Renal impairment (Creatinine Clearance less than 30ml per minute)
• Stratum B: Non-measurable disease
• Stratum C: Extramedullary plasmacytomas
• Stratum D: Central nervous system involvement

Phase

Phase 2

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

For each stratum, 95% credible intervals for the overall response rate (ORR) will be calculated and will utilise a minimally informative prior for the rate. A dual-criteria Bayesian proof-of-concept approach will be used to monitor and statistically analyse each stratum. Proof-of-concept (PoC) for the efficacy of the treatment in a stratum will be claimed if two criteria are met:

Stratum A or B:
(i) Observed overall response rate greater than or equal to 40%.
(ii) Posterior probability that the true response rate is greater than or equal to 30% (the futility rate), given the data, is greater than or equal to 0.90 (the level of proof).

Stratum C or D:
(i) Observed overall response rate greater than or equal to 30%.
(ii) Posterior probability that the true response rate is greater than or equal to 20% (the futility rate), given the data is greater than or equal to 0.90 (the level of proof).

40 patients will be recruited in each of strata A, B and C, but accrual to a stratum may be terminated early for proof of concept or for futility.

Monitoring the primary endpoint in each stratum will commence when at least 12 to 20 patients have completed 4 cycles (or have withdrawn).

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

20/06/2023

Actual

2/08/2023

Date of last participant enrolment

Anticipated

19/01/2025

Actual

Date of last data collection

Anticipated

19/01/2027

Actual

Sample size

Target

140

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Country [2]

Singapore

State/province [2]

Singapore

Country [3]

Taiwan, Province Of China

State/province [3]

Taibei

Country [4]

China

State/province [4]

Shanghai

Country [5]

China

State/province [5]

Beijing

Country [6]

Hong Kong

State/province [6]

Hong Kong

Country [7]