Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial Summary
This phase I/II trial studies the best dose of M3814 when given together with radium-223
dichloride or with radium-223 dichloride and avelumab and to see how well they work in
treating patients with castrate-resistant prostate cancer that had spread to other places in
the body (metastatic). M3814 may stop the growth of tumor cells by blocking some of the
enzymes needed for cell growth. Radioactive drugs, such as radium-223 dichloride, may carry
radiation directly to tumor cells and not harm normal cells. Immunotherapy with monoclonal
antibodies, such as avelumab, may help the body's immune system attack the cancer, and may
interfere with the ability of tumor cells to grow and spread. This study is being done to
find out the better treatment between radium-223 dichloride alone, radium-223 dichloride in
combination with M3814, or radium-223 dichloride in combination with both M3814 and avelumab,
to lower the chance of prostate cancer growing or spreading in the bone, and if this approach
is better or worse than the usual approach for advanced prostate cancer not responsive to
hormonal therapy.
Phase
Phase 1/Phase 2
Funding Agency/Sponsor
National Cooperative Group
Disease
Prostate, Bladder, and Kidney Cancers
Enrollment Eligibility
Inclusion Criteria:
- PHASE 1: Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky
>= 70%)
- PHASE 2: ECOG performance status =< 2 (Karnofsky >= 60%)
- Unless a patient has had orchiectomy by surgery, the patient is expected to be on
antiandrogen therapy (ADT) for "medical castration". ADT needs to be maintained
throughout the study. Testosterone level should be checked, and kept consistently
lower than 50 ng/dL, similar to that obtained with bilateral orchiectomy
- Progressive castration-resistant prostate cancer with two or more skeletal metastases
identified by 99mTC bone scintigraphy. One or more lymph node metastases allowed, but
not mandatory. Lymph node metastases in each individually must measure less than 3 cm
in the longest dimension. Visible visceral organ metastases are not allowed. A
diagnosis of prostate cancer must have been histologically confirmed at any time point
- Baseline prostatic specific antigen (PSA) level of 1 ng/mL or higher with evidence of
progressively increasing PSA values (two consecutive increases over the previous
reference value)
- Progression after at least one of the following: abiraterone, enzalutamide,
apalutamide, darolutamide, or taxane chemotherapy (docetaxel, cabazitaxel). There is
no maximum number of prior therapies. Prior immunotherapies (for example, Sipuleucel-T
or pembrolizumab) do not exclude the patient from participation
- Age >= 18 years. Castrate-resistant prostate cancer (CRPC) affects older adults and is
rarely encountered in children and adolescents
- Life expectancy >= 6 months
- Albumin > 2.5 mg/dL
- Hemoglobin > 9 mg/dL
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with the exception
of < 3 mg/dL for patients with Gilbert's disease)
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Creatinine =< 1.5 x institutional ULN OR
- Glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy (with no medications prohibited by this protocol [e.g. drug-drug
interactions]) with undetectable viral load within 6 months are eligible for this
trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy (with no medications prohibited by
this protocol [e.g. drug-drug interactions]), if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load (with no medications prohibited
by this protocol [e.g. drug-drug interactions])
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional classification. To be
eligible for this trial, patients should be class 2B or better
- Concomitant use of physiologic corticosteroids is allowed
- Concomitant use of bisphosphonates is allowed (use of bone health agents is mandatory
- either denosumab [preferred] or bisphosphonates)
- The effects of radium-223 dichloride, M3814, and avelumab on the developing human
fetus are unknown. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study participation,
and 6 months after completion of Radium-223 dichloride, M3814, and avelumab
administration
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
- Patients must be able to swallow orally administered medication
- Patients with asymptomatic, treated brain metastases are permitted if there is no
evidence of progression for at least 4 weeks after central nervous system
(CNS)-directed treatment, as ascertained by clinical examination and brain imaging
(magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the
screening period
Exclusion Criteria:
- Active autoimmune conditions or patients on chronic immunosuppression due to
underlying autoimmune condition
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Prior therapy with radionuclides (e.g., strontium, samarium, rhenium, radium)
- Patients who are receiving any other investigational agents
- Patients who have had previous hemibody external radiation
- Patients who have had systemic radiotherapy with radioisotopes
- Patients who have imminent/established spinal cord compression, pathological fracture
in weight bearing bones or bone lesion with soft tissue component unless treated as
appropriate with radiation and/or surgery before starting on trial
- Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to radium-223 dichloride, M3814, or avelumab
- Patients unable to discontinue medications or substances that are potent inhibitors,
inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to study treatment are
ineligible.
- Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must
be discontinued at least 1 week prior to first M3814 dose.
- Medications or substances that are strong inducers of CYP3A4/5 or CYP2C19 must be
stopped at least 3 weeks prior to the first M3814 dose.
- Drugs mainly metabolized by CYP3A with a narrow therapeutic index (as judged by
the Investigator or authorized designee) must be discontinued at least 1 day
prior to first M3814 dose.
- Note: Because the lists of these agents are constantly changing, it is important
to regularly consult a frequently- updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk
of interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the- counter medicine or
herbal product.
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Patients must not have an active infection requiring systemic treatment
- Patients must not use immunosuppressive medication =< 7 days of registration, EXCEPT
for the following:
- Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection)
- Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
- Patients who cannot discontinue concomitant H2 blockers or proton-pump inhibitors
(PPIs). Patients may confer with the study doctor to determine if such medications can
be discontinued. These must be discontinued >= 5 days prior to study treatment.
Patients do not need to discontinue calcium carbonate
- Patients receiving sorivudine or any chemically related analogues (such as brivudine)
are excluded
- Patients with a known history or present osteonecrosis of the jaw