Phase II Study of Sipuleucel-T and Indoximod for Patients With Refractory Metastatic Prostate Cancer

Phase 2

Completed

• Conditions: Metastatic Prostate Cancer
• Interventions: Biological: Indoximod; Biological: Sipuleucel-T; Other: Placebo

• Registration Number: NCT01560923
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

This is a randomized, double blind, multi-institutional phase II therapeutic study of Indoximod or placebo after the completion of standard of care sipuleucel-T (Provenge®) in men with asymptomatic or minimally symptomatic metastatic prostate cancer that is castration resistant (hormone refractory). Patients are randomized to receive either twice daily oral Indoximod or placebo for 6 months beginning the day after the third and final sipuleucel-T infusion.

Detailed Description

Sipuleucel-T will be administered as standard of care. Oral Indoximod/placebo will be self-administered twice daily for 6 months starting after the last infusion of sipuleucel-T. Patients will be treated for a minimum of 12 weeks of Indoximod/placebo before disease progression can be declared and Indoximod/placebo will not be discontinued for increasing prostate specific antigen (PSA) in the absence of symptomatic clinical progression.

Study Timeline

• Study First Submitted: 2012-03-20
• Study First Submitted QC: 2012-03-21
• Study First Posted: 2012-03-22
• Study Start: 2012-10-01
• Primary Completion: 2018-12-12
• Study Completion: 2018-12-12
• Status Verified: 2020-03
• Results First Submitted: 2020-03-06
• Results First Submitted QC: 2020-03-20
• Last Update Submitted: 2020-03-20
• Results First Posted: 2020-04-03
• Last Update Posted: 2020-04-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 47

Inclusion Criteria

• Histologically documented adenocarcinoma of the prostate with metastatic disease as evidenced by soft tissue and/or bony metastases on baseline computed tomography (CT) scan of the abdomen and pelvis and/or bone scan

• Castration-resistant based on a current or historical evidence of disease progression despite surgical or medical castration as demonstrated by one or more of the following:

  • PSA progression (defined as two consecutive prostate specific antigen (PSA) measurements at least 14 days apart ≥ 2.0 ng/ml and ≥ 50% above the minimum PSA during castration therapy or above pre-treatment value if no response)
  • progression of measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria (≥ 50% increase in the sum of the cross products of all measurable lesions or the development of any new lesions
  • progression of non-measureable disease

• Serum PSA ≥ 2.0 ng/ml at study enrollment

• Castration levels of testosterone defined as ≤ 30 ng/dL at study enrollment. Must be at least 3 months from surgical castration or must have received medical castration therapy for at least 3 months and be receiving such therapy at the time of confirmed disease progression

• Asymptomatic or minimally symptomatic disease as demonstrated by Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 and no need for opiate pain medications to control pain/symptoms

• Age 18 years and old

• Adequate bone marrow, renal and hepatic function within 14 days of study enrollment defined as:

  • Bone marrow: WBC > 3,000/uL; absolute neutrophil count > 1,500/uL; platelets > 100,000/uL
  • Renal: creatinine within institutional upper limit of normal (ULN) OR creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above ULN
  • Hepatic: total bilirubin < 1.5 X institutional ULN; aspartate aminotransferase (AST ((SGOT)) and alanine aminotransferase (ALT((SGPT)) < 2.5 X institutional ULN

Exclusion Criteria

• Chronic steroid dependence (should stop all steroid supplementation 4 weeks prior to enrollment)
• Human immunodeficiency virus (HIV)-positive patients and those with other acquired/inherited immunodeficiency
• History of gastrointestinal disease causing malabsorption or obstruction such as, but not limited to Crohn's disease, celiac sprue, tropical sprue, bacterial overgrowth/blind loop syndrome, gastric bypass surgery, strictures, adhesions, achalasia, bowel obstruction, or extensive small bowel resection
• Inability to take medications by mouth
• History of allergic reactions attributed to compounds of similar chemical or biologic composition
• Active autoimmune disease, chronic inflammatory condition, conditions requiring concurrent use of any systemic immunosuppressants or steroids. Mild-intermittent asthma requiring only occasional beta-agonist inhaler use or mild localized eczema will not be excluded.
• Previous allo-transplant of any kind
• History of prior treatment with anti-CTLA4 blocking antibody

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sipuleucel-T + Oral Indoximod	Indoximod	Oral Indoximod will be self-administered by mouth twice daily (1200 mg) for 6 months starting after the last (3rd) infusion of sipuleucel-T. Indoximod is a sterile tan powder compounded in capsule form of 200 mg.
Sipuleucel-T + Placebo	Sipuleucel-T	Placebo is identical-looking to Indoximod and provided in the same manner.
Sipuleucel-T + Placebo	Placebo	Placebo is identical-looking to Indoximod and provided in the same manner.
Sipuleucel-T + Oral Indoximod	Sipuleucel-T	Oral Indoximod will be self-administered by mouth twice daily (1200 mg) for 6 months starting after the last (3rd) infusion of sipuleucel-T. Indoximod is a sterile tan powder compounded in capsule form of 200 mg.

Primary Outcome Measures

Name	Time	Method
Immune Response to Sipuleucel-T	14 Weeks from First Leukapheresis	Assess the augmentation of immune response (PA2024) to sipuleucel-T measured at 14 weeks from first leukapheresis, in response to twice daily oral Indoximod at a dose of 1200 mg/day or an identical looking placebo.; The frequency of antigen specific, cytokine producing cells will be determined by an ELISPOT assay. ELISPOT assay will use whole PBMC to assess interferon gamma production in response to the immunizing protein PA2024. Increase in number of ELISPOT responses to PBMC in patients in the treatment arm will be compared to those in control arm.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Progression Free Survival at 6 Months	6 Months	Progression free survival (PFS) is a composite endpoint defined as disease progression in bone or soft tissues, PSA progression, worsening pain, or death. PFS will be measured in months from the time of study enrollment until the date of disease progression.; Progression is evaluated using the international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) \[Eur J Ca 45:228-247, 2009\]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
Objective Response Rate	4 weeks	rate as defined by Prostate Cancer Working Group -2 (PCWG2). ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST)(version 1.1) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm.; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesion.; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Overall Survival	2 years	To evaluate 2 year overall survival
Quality of Life Scale Results	6 Months	measured by the performance status with scale of 0-5 0 being 'normal activity' and 5 'being dead'
Ratio of Antibodies to PA2024	14 Weeks from First Leukapheresis	Assess the augmentation of immune response (PA2024) to sipuleucel-T measured at 14 weeks from first leukapheresis, in response to twice daily oral Indoximod at a dose of 1200 mg/day or an identical looking placebo.; The frequency of antigen specific, cytokine producing cells will be determined by an ELISPOT assay. ELISPOT assay will use whole PBMC to assess interferon gamma production in response to the immunizing protein PA2024.; Antibodies to PA2024 is measured by ELISA. The ratio of antibodies to ELISPOT responses to PBMC in patients in the treatment arm will be compared to those in control arm.

Trial Locations

Locations (4)

University of Illinois Medical Center; 🇺🇸 Chicago, Illinois, United States

Masonic Cancer Center, University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

Penn State Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

New York Presbyterian/Weill Cornell Medical Center; 🇺🇸 New York, New York, United States