Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma
Condition: Myeloma, Multiple; Myeloma-Multiple
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Avelumab; External beam radiotherapy
Intervention description: Avelumab 800 mg intravenous (IV) over 60 minutes (+/- 20 minutes) on days 1 and 15 of each 28-day cycle; 5 gray (Gy) per fraction will be delivered on 5 consecutive treatment days for a total dose 25 Gy
Intervention MeSH terms: Avelumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Monoclonal Antibody; Radiotherapy

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....
    

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 to 3 g/dL and/or bone marrow
             plasma cells greater than or equal to 10%, 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: Calcium (Ca) greater than or equal to10.5 mg/dL, or

               -  Lytic bone lesions on X-ray, computed tomography (CT), or positron emission
                  tomography (PET)/CT, or

               -  greater than or equal to 2 focal lesions on spinal magnetic resonance imaging
                  (MRI), or

               -  greater than or equal to 60% 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-cluster of differentiation (CD)38 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.

          -  Eastern Cooperative Oncology Group (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 upper limit of normal (ULN) (except
                  if due to myeloma)

        OR

          -  Measured creatinine clearance (CrCl) or estimated glomerular filtration rate (eGFR) by
             Chronic Kidney Disease Epidemiology Collaboration (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 (except if due to
             myeloma)

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than or
             equal to 2.5 X ULN (except if due to myeloma)

               -  The effects of avelumab on the developing human fetus are unknown, however, given
                  the known role of Programmed Cell Death Ligand 1 (PD-1)/Programmed death-ligand 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,
                  intrauterine device (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 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 radiation therapy (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 hepatitis B virus (HBV) deoxyribonucleic acid
                  (DNA) is undetectable

               -  Patients who are positive for hepatitis C virus (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 human
                  immunodeficiency virus (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 principal investigator (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.