Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma

Phase 2

Terminated

Conditions: Myeloma, Multiple
Myeloma-Multiple

Interventions: Biological: Avelumab
Radiation: External beam radiotherapy

Registration Number: NCT03910439

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Multiple myeloma is a cancer that forms from plasma cells which normally produce important immune response antibodies. It cannot be cured. Researchers hope the combination of radiation combined with the drug avelumab causes the immune system to kill myeloma cells more effectively.

Objective:

To see if avelumab given with radiation treatment helps treat multiple myeloma. Also to see if giving the treatments together is safe.

Eligibility:

People ages 18 and older with multiple myeloma that has come back after treatment and has spread to other parts of the body

Design:

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

Possible tumor biopsy

Bone marrow testing: A needle will be stuck into the participants hipbone to take out a small amount of marrow.

Positron emission tomography (PET)/Computed tomography (CT) scan and magnetic resonance imaging (MRI): Participants will lie in a machine that takes pictures of the body.

Participants will get avelumab through an intravenous (IV). An IV is a small plastic tube put into an arm vein. They will get avelumab every 2 weeks for 2 doses. Then they will get radiation each day for 5 days. They will continue to get avelumab every 2 weeks as long as they do not have bad side effects and the treatment is helping their disease.

Participants will have blood and urine tests, bone marrow biopsies, scans, and X-rays repeated during the study.

Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for up to 5 years....

Detailed Description: Background:

* Multiple Myeloma (MM) is a hematologic neoplasm of the plasma cells defined by an M- protein greater than or equal to 3.0 g/dL or bone marrow plasma cells greater than or equal to 10% and presence of end-organ disease.

* Although significant advances in treatment have been made in the past decade, MM remains incurable with median survivals of 5-8 years.

* While therapeutic strides have been made with approvals of immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies, treatment of relapsed refractory MM (RRMM) remains an unmet need for patients who have exhausted available therapies.

* Extramedullary plasmacytomas arising either from focal bone involvement or from hematogenous spread occur in 7-18% of newly diagnosed MM (NDMM) with an additional 6-20% in RRMM.

* Immune checkpoint inhibitors are being evaluated in combination regimens and evidence exists that radiation therapy (XRT) may synergize with immune checkpoint inhibitors.

Objectives:

- To assess the response rate of avelumab in combination with XRT (BavXRT) in RRMM patients with plasmacytomas or lytic lesions

Eligibility:

* Patients must have previously treated RRMM refractory to, ineligible for, or intolerant of available therapeutic regimens known to provide clinical benefit (e.g, immunomodulatory \[IMiD\], proteasome inhibitor, and anti-cluster of differentiation (CD)38 monoclonal antibody-based treatments).

* Presence of greater than or equal to 1 extramedullary plasmacytoma and/or lytic lesion amenable to XRT

* Age greater than or equal to 18 years

* Adequate organ function, and without serious comorbidity or disease (e.g., autoimmune disease), that would preclude concurrent systemic treatment or radiotherapy.

Design:

* Treatment will consist of a 4-week lead-in with avelumab, followed by concurrent XRT 5 gray (Gy) x 5 days). Monotherapy avelumab will continue indefinitely until progressive disease (PD) or unacceptable toxicity; 28-day cycles.

* Routine safety and MM-specific clinical labs will be assessed. Additional research bloods will be collected for evaluating immune-subsets, endosomes, and peripheral blood T cell repertoire prior to and following treatment (lead-in and prior to XRT, at disease re- evaluations at at time of response \[i.e., complete remission (CR)/progressive disease (PD)\]).

* Bone marrow biopsies will be evaluated for Programmed death-ligand 1 (PD-1)/ligand 1 (L1) expression, and B and T cell subsets using immunohistochemistry (IHC). Flow cytometry will also be used to evaluate stimulatory and inhibitory immune subsets along with endosomes. Standard clinical histopathology and flow cytometry will also be evaluated.

* Single arm, Simon minimax two-stage phase II trial design. The first stage will enroll 13 patients; if futility is not met, second stage will enroll another 14 patients to define the response rate to BavXRT in this population. Early stopping rules for safety will also be applied.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/Avelumab 800 mg intravenous (IV) every two weeks in combination with radiation therapy	Avelumab	Avelumab 800 mg IV every two weeks in combination with radiation therapy
1/Avelumab 800 mg intravenous (IV) every two weeks in combination with radiation therapy	External beam radiotherapy	Avelumab 800 mg IV every two weeks in combination with radiation therapy

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	up to end of study, an average of 11 months	ORR is defined as participants who experience a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) per International Myeloma Working Group Criteria (IMWG) 2016 criteria. Complete Response is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow aspirates. Stringent Complete Response is defined as complete response as noted previously plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immune-histochemistry. Partial Response is ≥50% reduction of serum M-protein plus reduction in 24 hour(h) urinary M-protein by ≥90% or to \<200 mg per 24 h. Very Good Partial Response is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 h.

Secondary Outcome Measures

Name	Time	Method
Fraction of Participants Who Experience a Minimal Residual Disease Negative (MRDneg)Complete Response (CR) Using the Study Treatment	up to up to end of study for individual patient, an average of 11 months	Response was assessed by the International Myeloma Working Group Criteria (IMWG) 2016 criteria. Sustained MRDnegCR is defined as negativity in the marrow (next-generation flow (NGF) or next-generation sequencing (NGS), or both) and by imaging confirmed minimum of 1 year apart.
Fluorodeoxyglucose (FDG) Avidity Positron-Emission Tomography/Computed Tomography (PET/CT) of Non-irradiated Extramedullary Lesions (Abscopal Effect) Compared to Baseline	End of study	FDG avidity of extramedullary lesions.
Fraction of Participants Who Experience a Complete Response (CR) or Stringent Complete Response (sCR) Using the Study Treatment	up to end of study for individual patient, an average of 11 months	Response was assessed by the International Myeloma Working Group (IMWG) response criteria, 2016. Complete Response is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow aspirates. Stringent Complete Response is defined as complete response as noted previously plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow biopsy by immune-histochemistry.
Number of Participants Overall Best Response	4 weeks	Response was assessed by the International Myeloma Working Group (IMWG) response criteria, 2016. Minimal Response is ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50-89%; in addition, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required. Stable Disease is not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease. And Progressive Disease is appearance of a new lesion(s), ≥50% increase from nadir in sum of the products of diameters (SPD) of \>1 lesion, or ≥50% increase in the longest diameter of a previous lesion \>1 cm in short axis; ≥50% increase in circulating plasma cells (minimum of 200 cells per microliter (μL) if this is the only measure of disease.
Percent Change in Aberrant Circulating Plasma Cells in the Peripheral Blood (PB) and Bone Marrow (BM) From Baseline	Baseline and up to end of study for individual patient, an average of 11 months	Blood samples and bone marrow samples were taken from participants and processed by flow cytometry.
Percent Reduction in Size of On-irradiated Extramedullary Lesions	end of study	Radiographic reduction in size of non-irradiated extramedullary lesions.
Number of Participants With Grade ≥1 Non-serious Adverse Events	Date treatment consent signed to date off study, approximately 14 months and 4 days.	Grade ≥1 non-serious adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. Grade 1 is mild, Grade 2 is moderate, and Grade 3 is severe or medically significant.
Progression-free Survival (PFS)	End of study, an average of 11 months	PFS was defined as those who progress or die without progression as failures, and censoring those who do not. Progressive disease was assessed by the 2016 International Myeloma Working Group (IMWG) response criteria and is an increase of 25% from lowest confirmed response value in one or more of the following criteria: Serum M-protein (absolute increase must be ≥0·5 g/dL); Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; Urine M-protein (absolute increase must be ≥200 mg/24 h); In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be \>10 mg/dL).
Percentage of Participants With Overall Survival (OS)	Enrollment through end of study, an average of 11 months	Participants who are alive following enrollment and study treatment.