This is a single-institution, single-arm, open-label Phase 2 trial evaluating evofosfamide in subjects with M1 CRPC who fail first-line ARSIs. In those progressing after second-line Docetaxel or deemed ineligible to it, the use of alternate ARSI remains the most common line of therapy in our Province, in keeping with recent international recommendations. After baseline molecular imaging (PSMA and fluorodeoxyglucose (FDG) PET/CT), prior to evofosfamide initiation, subjects will be encouraged to undergo biopsy of a dominant lesion: FDG-, PSMA-uptake and/or conventional imaging determined (in order, and according to feasibility). Subjects will then receive the alternate ARSI (i.e., different from the one received in first line) as per current standard practice and Provincial drug plan coverage. Additionally, subjects will receive combinatorial evofosfamide at a dose of 480 mg/m2 intravenously (IV) over 60 minutes on Days 1, 8 and 15 of every 28-day cycle. Therapy will continue until disease progression, unacceptable toxicity as a result of evofosfamide, or subject withdrawal. Assessments during evofosfamide treatment will include history, physical exam, and blood tests at each monthly visit to monitor for toxicity. Response and progression will be evaluated by whole-body PSMA PET/CT scan every 8 weeks (± 3 days) and determined using (PE)RECIST v1.1 criteria. PSA, NE markers (e.g., Serum CHGA, NSE), organ function tests (e.g., liver, kidney) and investigational liquid biopsy samples will be followed every cycle (monthly). FDG PET/CT will be performed at baseline, at 6-10 weeks from the date of signing the informed consent form (ICF), and upon progression, irrespective of treatment discontinuation or initiation of another therapy. Subjects will be followed for survival endpoints following completion of this study treatment until death.
At least 18 years of age;
Ability to understand the purposes and risks of the trial and has signed a written ICF approved by the investigator's REB;
CRPC stage M1 based on conventional imaging (CT and/or bone scan) or PSMA PET;
Progression (i.e., PSA rise of 25% or more, and absolute increase of 2 ng/mL or more from the nadir) to first-line ARSIs (Abi or Enza or Daro or Apa monotherapy) and subsequent docetaxel or deemed ineligible for it;
Myocardial infarction within 6 months prior to date of enrollment.
Current severe or unstable angina.
New York Heart Association Functional Classification III/IV. (Note: 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.)
Severe chronic obstructive or other pulmonary disease with hypoxemia at rest (requires supplementary oxygen, symptoms due to hypoxemia).
Single group
Evofosfamide
DrugThis study is evaluating evofosfamide in subjects with M1 CRPC who fail first-line ARSIs.
Preliminary clinical efficacy measures of evofosfamide in subjects with CRPC progressing to first-line ARSIs +/- docetaxel
Preliminary clinical efficacy measures of evofosfamide in subjects with CRPC (Castrate Resistant Prostate Cancer) progressing to first-line ARSIs (Androgen Receptor Signaling Inhibitor) +/- docetaxel will be determined. This is measured by the biochemical response rate (if the PSA (tumor marker) declined ≥50% compared to baseline). Sample(s) may be drawn with serum biochemistry sample(s).
Radiological (morphological and molecular) response rates
Radiologic response rates (morphologic and molecular) measured using (PE)RECIST (Response evaluation criteria in solid tumors) criteria v1.1 on prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/ computerized tomography (CT).
Professional free survival (PFS)
PFS (progression free survival) from time of first evofosfamide treatment until biochemical \[increase in PSA (tumor marker) \>25% or an absolute increase of \>2 ng/mL over baseline or nadir\].
Response rate and PFS (progression free survival) to subsequent therapies (PFS2)
Radiological or clinical progression; occurrence rate and time-to-event of NEPC phenotype based on histological (e.g., small cell NEPC or adenocarcinoma with \>50% staining to CHGA and/or SYP and/or NSE), clinical (e.g., development of visceral metastases without biochemical progression) or biochemical (e.g., serum CHGA level \>5× and/or NSE \>2× UNL); response rate and PFS2.
OS (overall survival)
OS (overall survival) as time from first treatment until death.
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University Health Network, Toronto
Lead sponsor
ImmunoGenesis
Collaborator
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