Patient case: 70-year-old male with prostate cancer; genetic feature: PTEN

Clinical trial: Selinexor (KPT-330) in Patients With Metastatic Castration-Resistant Prostate Cancer and Prior Therapy With Abiraterone and/or Enzalutamide

Summary: Abiraterone acetate is now considered the standard of care for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the pre-chemotherapy setting. Patients with primary or acquired abiraterone resistance typically have rapidly progressive, refractory disease for which limited treatment options are available. The development of new therapies in mCRPC requires a focus on patients with primary or acquired resistance to abiraterone. Patients with abiraterone-refractory mCRPC have a poor prognosis overall with median survival after progression of disease at approximately 19 months. While chemotherapy is a standard approach in this setting, it is refused by many patients and clinicians due to toxicity concerns.
  Selinexor is a first in class Selective Inhibitor of Nuclear Export (SINE) that specifically blocks the karyopherin protein Exportin 1 (XPO1/Exportin 1). XPO1 is a key regulatory protein responsible for the nuclear export leading to functional inactivation of tumor suppressor proteins (TSPs) and is up-regulated 2-4 fold in all cancers studied to date. Selinexor, given orally, has demonstrated potent anti-cancer activity in animal models of prostate cancer including inhibition of PC3 driven bone metastasis.The goal of this trial is to evaluate the potential for a progression free survival benefit associated with Selinexor administration in patients with abiraterone-refractory mCRPC.
  Single agent phase II open label study of Selinexor in patients with mCRPC with prior therapy with standard hormone ablation agents and abiraterone. A maximum of 54 evaluable patients will be accrued for this study, provided the early stopping criteria are not met.
  The starting dose for all patients will be an oral dose of 65 mg/m2, given twice per week at least 48 hours apart. Tablets for Selinexor oral administration will be supplied in two (2) strengths: 10 and 25 mg of active ingredient per tablet. Dexamethasone will be coadministered at a dose of 2 mg twice daily on the day of dosing and the day after.
  Patients will be followed for 30 days after completion of treatment or removal from study, or until death, whichever occurs first. Patients removed from study for unacceptable treatment related adverse event(s) will be followed until resolution or stabilization of all treatment related adverse events to Grade 2 or lower.


Eligibility: Inclusion Criteria:
  -  Age ≥ 18 years.
  -  Histologically confirmed adenocarcinoma of the prostate.
  -  Patients must have castrate levels of testosterone (< 50 ng/dL) on GnRH analogues or have had prior orchiectomy. GnRH analogues must be continued while on study.
  -  Progressive disease as demonstrated by a rising PSA (at least two determinations) prior to study entry, and/or radiographic evidence of tumor progression in soft tissue according to modified RECIST criteria or identification of new lesions by bone scan (i.e., ≥ 2 new lesions).
  -  Primary resistance or acquired resistance (i.e., acquired resistance will be defined as disease progression following a period of response defined as ≥50% decline in PSA within 12 weeks of starting therapy and not otherwise meeting criteria for primary resistance) to any of the following agents/combinations of therapy:
  -  Abiraterone acetate. Primary resistance to abiraterone will be defined as:
  -  No PSA decline
  -  PSA decline less than 50% after 12 weeks of abiraterone therapy
  -  PSA progression within 12 weeks of AA treatment (by PCWG2 criteria), after initial response to therapy
  -  Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone treatment
  -  Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting abiraterone treatment
  -  Enzalutamide. Primary resistance to enzalutamide will be defined as:
  -  No PSA decline
  -  PSA decline less than 50% after 12 weeks of enzalutamide therapy
  -  PSA progression within 12 weeks of enzalutamide treatment (by PCWG2 criteria), after initial response to therapy
  -  Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting enzalutamide treatment
  -  Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting enzalutamide treatment
  -  Combination therapy with abiraterone and enzalutamide. Primary resistance to combination therapy with abiraterone and enzalutamide will be defined as:
  -  No PSA decline
  -  PSA decline less than 50% after 12 weeks of abiraterone and enzalutamide therapy
  -  PSA progression within 12 weeks of abiraterone and enzalutamide treatment (by PCWG2 criteria), after initial response to therapy
  -  Objective progression, by RECIST criteria for soft tissue lesions and by modified PCWG2 criteria for bone lesions within 12 weeks of starting abiraterone and enzalutamide treatment
  -  Unequivocal clinical progression (per the treating provider's discretion) within 12 weeks of starting abiraterone and enzalutamide treatment
  -  Sequenced therapy, including either of the following:
  -  Abiraterone acetate followed by enzalutamide
  -  Primary resistance will be defined per criteria for abiraterone monotherapy primary resistance, section 3.3.1, item 5a
  -  Enzalutamide followed by abiraterone acetate
  -  Primary resistance will be defined per criteria for enzalutamide monotherapy primary resistance, section 3.3.1, item 5b
  -  Presence of 1 or more bone metastasis.
  -  ECOG Performance status 0 or 1.
  -  Prior and ongoing zoledronic acid or denosumab therapy is allowed.
  -  Prior therapy with radium-223 is allowed.
  -  Discontinuation of prior therapy for mCRPC: A Washout period of 5 half-lives or 4 weeks for the following therapies (whichever is shorter) is required: Abiraterone, enzalutamide, fluconazole, itraconazole, flutamide, bicalutamide, nilutamide, and other experimental hormonal agents (ARN509, TAK-700, etc.), sipuleucel-T (Provenge), other experimental vaccines (PROSTVAC-V/F, etc.), Strontium-89, Samarium, and Radium-223 chloride.
  -  Baseline laboratory parameters:
  Adequate bone marrow function:
  Leukocytes > 3,000/mcL absolute neutrophil count > 1,500/mcL Platelets > 125,000/mcL Hemoglobin ≥ 5.59 mmol/L or 9 g/dL Up to 5% deviation is tolerated. Transfusions and growth factors are allowed.
  Adequate hepatic function:
  Total bilirubin within normal institutional limits Alkaline phosphatase < 4 X institutional upper limit of normal AST(SGOT) < 3 X institutional upper limit of normal ALT(SGPT) < 3 X institutional upper limit of normal
  Adequate renal function:
  Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  -  Ability to understand a written informed consent document, and the willingness to sign it
  -  Life expectancy of at least 12 weeks
  -  Able to swallow and retain oral medication
  Exclusion Criteria:
  -  Untreated brain metastases. Brain metastases ≤1 cm and not associated with any focal neurologic deficits are allowed.
  -  Prior docetaxel or other chemotherapy for mCRPC
  -  Active or symptomatic viral hepatitis or chronic liver disease
  -  Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or known cardiac ejection fraction measurement of <50 % at baseline.
  -  Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea or other gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of the study agents
  -  Pure small cell carcinoma of the prostate or any mixed histology cancer of the prostate (eg: neuroendocrine) that contains <50% adenocarcinoma, as observed on biopsy obtained at the time of diagnosis or on any subsequent biopsies.
  -  Any "currently active" second malignancy, other than non-melanoma skin cancer. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next year.
  -  Any condition, which in the opinion of the investigator, would preclude participation in this trial.
  -  Active psychiatric illnesses/social situations that would limit compliance with protocol requirements.
  -  Patients in whom urgent treatment with docetaxel is indicated, per clinician discretion. This includes, but is not limited to patients with symptomatic visceral metastatic disease
  -  Uncontrolled infection or concomitant medical illness that is not adequately controlled with current medical management, as determined per clinician discretion.
  -  Active bleeding disorders or evidence of evidence of chronic or acute disseminated intravascular coagulation (DIC)
  -  Severely compromised immunological state, including known human immunodeficiency virus (HIV)
  -  Any acute toxities due to prior anti-cancer treatments and/or radiotherapy that have not resolved to a NCI CTCAE Grade of ≤1 (except alopecia)
  -  Prior radiation therapy completed <3 weeks or single fraction of palliative radiotherapy <14 days prior to first dose of KPT-330
  -  Initiation of bisphosphonate therapy <4 weeks prior to first dose of KPT-330. Patients receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks prior to first dose of KPT-330.
  -  Men unable or unwilling to employ 2 forms of highly effective contraception throughout the study and for 8 weeks after the end of study treatment

Relevance to patient case: not relevant