Clinical Trials /

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

NCT03910439

Description:

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 participant s hipbone to take out a small amount of marrow. PET/CT scan and MRI: Participants will lie in a machine that takes pictures of the body. Participants will get avelumab through an 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....

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma
  • Official Title: A Phase II Pilot Study of Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: 190078
  • SECONDARY ID: 19-C-0078
  • NCT ID: NCT03910439

Conditions

  • Myeloma, Multiple
  • Myeloma-Multiple

Interventions

DrugSynonymsArms
Avelumab1

Purpose

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 participant s hipbone to take out a small amount of marrow. PET/CT scan and MRI: Participants will lie in a machine that takes pictures of the body. Participants will get avelumab through an 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-CD38 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 5Gy
           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- evalutions at at time of response [i.e., CR/PD]).

        -  Bone marrow biopsies will be evaluated for PD-1/L1 expression, and B and T cell subsets
           using 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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalAvelumab 800 mg IV every two weeks in combination with radiation therapy
  • Avelumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have a documented diagnosis of multiple myeloma defined by the
             International Myeloma Working Group Criteria (IMWG)(3). Patients at initial diagnosis
             must have had a serum M-protein greater than or equal to3 g/dL and/or bone marrow
             plasma cells greater than or equal to10%, and at least one of the following:

               -  Anemia: Hemoglobin less than or equal to10 g/dL, or

               -  Renal failure: serum creatinine greater than or equal to 2.0 mg/dL, or

               -  Hypercalcemia: Ca greater than or equal to10.5 mg/dL, or

               -  Lytic bone lesions on X-ray, CT, or PET/CT, or

               -  greater than or equal to2 focal lesions on spinal MRI, or

               -  greater than or equal to60% bone marrow plasma cells, or

               -  Involved/un-involved serum free light chain ratio greater than or equal to 100

          -  Have at least one extramedullary plasmacytoma or lytic lesion which at the discretion
             of the investigators is amenable to and clinically indicated for localized radiation
             therapy

          -  Must have Relapsed or Relapsed and Refractory Multiple Myeloma. Patients must have
             documented evidence of progressive disease (PD) as defined by the IMWG criteria on or
             after their last regimen and must have achieved a minimal response (MR) or better to
             at least one prior regimen. Definitions by the IMWG:

               -  Relapsed and refractory: disease that is nonresponsive while on salvage therapy
                  or progresses within 60 days of last therapy in patients who have achieved minor
                  response (MR) or better

               -  Relapsed: disease that progresses and requires the initiation of salvage therapy
                  but does not meet criteria for either primary refractory or relapsed and
                  refractory MM categories

          -  Patients must have been previously treated for MM and be refractory to, not a
             candidate for (ineligible), or intolerant of available therapeutic regimens known to
             provide clinical benefit including immunomodulatory (IMiD), proteasome inhibitor, and
             anti-CD38 monoclonal antibody-based treatments.

          -  Documented measurable disease within the 4 weeks prior to registration defined by any
             one of the following:

               -  Monoclonal Bone marrow plasma cells greater than or equal to 5%

               -  Serum monoclonal protein greater than or equal to 0.2 g/dl

               -  Urine monoclonal protein >200 mg/24 hour

               -  Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio

               -  A measurable lesion on PET/CT or MRI

          -  Be greater than or equal to 18 years of age on day of signing informed consent

        Note: The estimated 2017 US incidence of MM of patients under the age of 20 is 0.0%;
        therefore, children are excluded from enrollment in this study.

          -  ECOG performance status less than or equal to 2

          -  Adequate organ function as evidenced by the following laboratory parameters:

               -  Absolute neutrophil count (ANC) greater than or equal to 1000 /mcL

               -  Platelets greater than or equal to 75,000 / mcL

               -  Hemoglobin greater than or equal to 8 g/dL (transfusions permitted)

               -  Serum creatinine less than or equal to (1.5 X ULN)

        OR

          -  Measured CrCl or eGFR by CKD- EPI formula may be used to estimate CrCl/eGFR greater
             than or equal to 30 mL/min/1.73 m(2) for subject with creatinine levels > 1.5 X ULN

          -  Serum total bilirubin less than or equal to 1.5 X ULN OR Direct bilirubin less than or
             equal to ULN for patients with total bilirubin levels > 1.5 ULN

          -  AST (SGOT) and ALT (SGPT) less than or equal to 2.5 X ULN

               -  The effects of avelumab on the developing human fetus are unknown, however, given
                  the known role of PD-1/PD-L1 in maintaining the maternal/fetal tolerance,
                  avelumab can be expected to have an adverse effect on pregnancy, including
                  embryo-lethality. Women of child-bearing potential (WOCBP) and men must agree to
                  use highly effective contraception (such as implants, injectables, combined oral
                  contraceptives, IUDs, sexual abstinence or vasectomised partner) prior to study
                  entry and for the duration of study treatment, and for at least 30 days after the
                  last dose of avelumab. Should a woman become pregnant or suspect she is pregnant
                  while she or her partner is participating in this study, she should inform her
                  treating physician immediately.

        NOTE: WOCBP is defined as any female who has experienced menarche and who has not undergone
        successful surgical sterilization or who is not postmenopausal.

          -  Negative serum or urine pregnancy test at screening for WOCBP.

          -  Ability of patient or Legally Authorized Representative (LAR) to understand and the
             willingness to sign a written informed consent document

        EXCLUSION CRITERIA:

          -  Patients with clinically unstable lesions (e.g., impending cord compression) where a
             delay in receiving XRT would be detrimental are not eligible

          -  Current or prior anti-cancer treatment prior to the first dose of avelumab as defined
             below:

               -  Chemotherapy, targeted small molecule therapy, or other anti-cancer treatment not
                  otherwise specified below within 2 weeks

               -  Radiation therapy within 2 weeks

               -  Anti-cancer monoclonal antibody (mAb) treatment within 4 weeks

               -  Use of an investigational agent (e.g., biologic, drug, or other) within 4 weeks

               -  Allogeneic stem cell transplant

          -  No autoimmune disease, as follows:

               -  Active (acute or chronic) autoimmune disease that might deteriorate when
                  receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo,
                  psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive
                  treatment may be eligible.

               -  History of serious autoimmune-related disorders including immune colitis,
                  inflammatory bowel disease, pneumonitis, or pulmonary fibrosis whether drug-
                  mediated or not.

          -  Current use of immunosuppressive medication, EXCEPT for the following:

               -  Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
                  intra-articular injection)

               -  Systemic corticosteroids at physiologic doses

               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)

          -  Uncontrolled intercurrent illness including, but not limited to the following that may
             limit interpretation of results or that could increase risk to the patient in the
             judgment of the investigator:

               -  Patients with a positive hepatitis B core antibody [HBcAb] and negative surface
                  antigen (HBsAg) may be included if HBV DNA is undetectable

               -  Patients who are positive for HCV antibody must be negative for HCV by polymerase
                  chain reaction (PCR) to be eligible for study participation

               -  Known acquired immunodeficiency syndrome (AIDS). Controlled and stable HIV
                  positivity is allowed

               -  Prior organ transplantation including allogenic stem-cell transplantation

               -  Clinically significant cardiovascular disease: cerebral vascular accident/stroke
                  (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to
                  enrollment), unstable angina, congestive heart failure (greater than or equal to
                  New York Heart Association Classification Class III), or serious cardiac
                  arrhythmia requiring medication. Mild arrhythmias, e.g. stable atrial
                  fibrillation, may be allowed at the discretion of the investigator

               -  Active infection requiring systemic therapy (minor infections may be allowed at
                  the discretion of the investigator)

               -  Known mental or physical illness that would interfere with cooperation with the
                  requirements of the trial or confound the results or interpretation of the
                  results of the trial and, in the opinion of the treating investigator, would make
                  the patient inappropriate for entry into the study.

          -  Persisting toxicity related to prior therapy (Grade > 1); however, alopecia, sensory
             neuropathy Grade less than or equal to 2, or other Grade less than or equal to 2 not
             constituting a safety risk based on investigator s judgment are acceptable.

          -  Vaccination with live vaccines within 4 weeks of the first dose of avelumab and while
             on study is prohibited (inactivated vaccines may be administered).

          -  Pregnant or lactating females. Because there is an unknown but potential risk for
             adverse events in nursing infants, on-study breastfeeding is not allowed.

          -  History of allergic reactions or hypersensitivity to avelumab or any component in its
             formulations, including known severe hypersensitivity reactions to monoclonal
             antibodies (Grade greater than or equal to 3) unless felt to be in the best interests
             of the patient at the discretion of the investigator.

          -  Known additional malignancy that is symptomatic or requires active systemic treatment
             (at the discretion of the PI, exceptions may be made if in the best interest of the
             patient).

          -  Other severe acute or chronic medical conditions including immune colitis,
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
             conditions including recent (within the past year) or active suicidal ideation or
             behavior; or laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:every 6-8 weeks
Safety Issue:
Description:The fraction of patients who experience a partial response (PR), very good partial response (VGPR), complete response (CR), or stringent complete response (sCR) per IMWG 2016 criteria.

Secondary Outcome Measures

Measure:Complete Response (CR) rate and Minimal Residual Disease (MRD) negative CR rate
Time Frame:every 6-8 weeks
Safety Issue:
Description:the fraction of patients who experience a CR or sCR using the study treatment
Measure:Reductions in bone marrow (BM) and peripheral blood (PD) plasmacytosis
Time Frame:every 6-8 weeks
Safety Issue:
Description:the fraction of patients who experience an MRDnegCR using the study treatment
Measure:Radiographic reduction in size, and/or FDG avidity (PET/CT) of extramedullary lesio
Time Frame:every 6-8 weeks
Safety Issue:
Description:percent change in plasma cells in the PB and BM from baseline
Measure:Radiographic reduction in size, and/or FDG avidity (PET/CT) of non-irradiated extramedullary lesions (abscopal effect)
Time Frame:every 6-8 weeks
Safety Issue:
Description:percent reduction of size, and/or FDG avidity, radiographicaly, of extramedullary lesions compared to baseline
Measure:Progression-free survival (PFS)
Time Frame:every 6-8 weeks
Safety Issue:
Description:determined using the Kaplan- Meier method, considering those who progress or die without progression as failures, and censoring thosewho do not.
Measure:Overall survival (OS)
Time Frame:ongoing
Safety Issue:
Description:will be determined using the Kaplan-Meier method
Measure:All Grade, Grade 3-4, and serious adverse events
Time Frame:ongoing
Safety Issue:
Description:overall tolerability in terms of adverse events will be evaluated with descriptive statistics to determine the safety of receiving avelumabin the context of irradiation
Measure:ORR post cycle 1 (prior to XRT)
Time Frame:4 weeks
Safety Issue:
Description:a milestone ORR at start of cycle 2 will be calculated as above to determine ORR of avelumab monotherapy after 1 cycle of therapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Monoclonal Antibody
  • Radiotherapy

Last Updated

October 29, 2019