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Ipilimumab With Nivolumab for Molecular-selected Patients With Castration-resistant Prostate Cancer (INSPIRE)

Primary Purpose

Prostatic Neoplasms, Castration-Resistant

Status
Recruiting
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Ipilimumab
Nivolumab
Sponsored by
Radboud University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostatic Neoplasms, Castration-Resistant focused on measuring mCRPC, Immune checkpoint inhibitors, Immunotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

  1. Written informed consent.
  2. Histological diagnosis of adenocarcinoma of the prostate. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.
  3. Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease defined either as measurable disease by RECIST1.1 criteria or presence of bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable disease is compulsory.
  4. An immunogenic phenotype, consisting of one of the next criteria: 1, mismatch repair deficiency and/or a high mutational burden of >7 mutations per Mb (cluster A); 2, BRCA2 inactivation or BRCAness signature (cluster B); 3, a tandem duplication signature and/or CDK12 biallelic inactivation (cluster C)
  5. Age ≥18 years.
  6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  7. PSA ≥ 2 ng/ml.
  8. Documented willingness to use an effective means of contraception while participating in the study and for 7 months post last dose of treatment
  9. Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM).
  10. Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment.
  11. Progression of disease by:

    1. PSA utilizing PCWG3 criteria
    2. Bone scan: disease progression as defined by at least 2 new lesions on bone scan.
    3. Soft tissue disease progression defined by modified RECIST 1.1.
    4. Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases.
  12. Having a biopsiable metastatic lesion and willingness to undergo a baseline* and on treatment tumour biopsy for next-generation sequencing and biomarker analyses.

    • When sufficient FFPE material is available from a biopsy in castrate-state, one may apply for a waiver for a new baseline biopsy.

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

  1. Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1 antagonists) for cohort 1. For cohort 2, patients may have prior treatment with monotherapy CTLA-4 or PD-1 or PD-L1.
  2. Surgery or chemotherapy within 4 weeks prior to trial entry / randomisation into the study. Any other therapies for prostate cancer, other than GnRH analogue therapy and osteoporosis preventing agents, are not allowed.
  3. Radiotherapy within 2 weeks prior to trial entry. Radiation-related side effects higher than grade 1, or above baseline.
  4. Participation in another interventional clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry/randomisation.
  5. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.
  6. Untreated or symptomatic brain or leptomeningeal involvement.
  7. Inadequate organ and bone marrow function as evidenced by:

    1. hemoglobin <6.2 mmol/L
    2. Absolute neutrophil count <1.0 x 109/L
    3. Platelet count < 75 x 109/L
    4. Albumin <30 g/dL.
    5. AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥ 5 x ULN if liver metastases present)
    6. Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert's disease)
    7. Serum Creatinine > 1.5 x ULN
  8. Any of the following cardiac criteria; a. Any clinically significant abnormalities in rhythm conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block) c. Experience of any of the following procedures or conditions in the preceding six months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, congestive heart failure NYHA ≥ Grade2 d. Uncontrolled hypotension defined as systolic blood pressure (BP) <90mmHg and/or diastolic BP <50mmHg
  9. Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
  10. History of clinically relevant auto-immune disease (including Crohn's disease or ulcerative colitis). Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of nivolumab or ipilimumab or that may affect the interpretation of the results or renders the patients at high risk from treatment complications.
  11. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase.
  12. Malignancies other than prostate cancer within 3 years prior to trial entry / randomization, except for adequately treated basal or squamous cell skin cancer and non-muscle invasive bladder cancer.
  13. Active second malignancy, except basal or squamous cell skin cancer and non-muscle invasive bladder cancer. Other treated malignancies with curative intent, including colorectal cancer, may be included following PI consent.
  14. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy.
  15. Inability to comply with study and follow-up procedures.
  16. Patients with predominant small cell or neuroendocrine prostate cancer are not eligible.
  17. Patients without measurable lesion per RECIST1.1, and with a superscan on bone scintigraphy not evaluable per PCWG3 criteria, are not eligible

Sites / Locations

  • RadboudumcRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

Combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg, followed by nivolumab 480mg flat dose (Q4w) to up to one year. This regimen will be given to participants in both cohort 1 and 2.

Outcomes

Primary Outcome Measures

Efficacy endpoint: DCR
Disease control rate (DCR) of >6mo; this includes a change from baseline in tumour volume as measured by SD, PR or CR by best ORR in evaluable participants, all lasting longer than 6mo

Secondary Outcome Measures

Safety endpoint: adverse effects
Percentage of Grade 3/4 and 5 treatment-related adverse effects
Efficacy endpoint: ORR
Best objective response rate (ORR) per RECIST1.1 criteria
Efficacy endpoint: BRR
Biochemical response rate (BRR) at week 13 and maximal PSA decline according to PCWG3 criteria
Efficacy endpoint: rPFS
Radiographic progression free survival per irRECIST1.1 immune-related response criteria

Full Information

First Posted
January 6, 2021
Last Updated
November 16, 2021
Sponsor
Radboud University Medical Center
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT04717154
Brief Title
Ipilimumab With Nivolumab for Molecular-selected Patients With Castration-resistant Prostate Cancer
Acronym
INSPIRE
Official Title
Phase 2 INSPIRE Trial: Ipilimumab With Nivolumab for Molecular- Selected Patients With Castration-resistant Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Recruiting
Study Start Date
January 19, 2021 (Actual)
Primary Completion Date
January 31, 2025 (Anticipated)
Study Completion Date
June 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Radboud University Medical Center
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the effects of 4 cycles of combinatory immunotherapy (ipilimumab and nivolumab), followed by monotherapy nivolumab in participants with immunogenic metastatic castration-resistant prostate cancer.
Detailed Description
Following molecular characterization (next-generation sequencing) a total of 75 mCRPC patients with a putative immunogenic subtype will be included within the phase 2 INSPIRE trial. As treatment we will be utilizing a combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg for 4 doses, followed by nivolumab 480mg flat dose for up to one year. All participants will additionally undergo an on-trial metastatic tissue biopsy. Translational research will study immunological correlates and in-depth genomic/transcriptomic and multispectral immunohistochemical analyses of immune infiltrate.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostatic Neoplasms, Castration-Resistant
Keywords
mCRPC, Immune checkpoint inhibitors, Immunotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Open label, single treatment, phase II study: Cohort A1 will assess the efficacy of ipilimumab+nivolumab in mCRPC patients with RECIST1.1 measurable disease that are naïve for immune checkpoint inhibition Cohort A2 will assess the efficacy of ipilimumab+nivolumab in patients without RECIST1.1 measurable disease that are naïve for immune checkpoint inhibition Cohort B will assess the efficacy of ipilimumab+nivolumab in patients with RECIST1.1 measurable disease and prior progression to immune checkpoint inhibitor monotherapy (CTLA-4 or anti-PD1/PDL1)
Masking
None (Open Label)
Allocation
N/A
Enrollment
75 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
Combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg, followed by nivolumab 480mg flat dose (Q4w) to up to one year. This regimen will be given to participants in both cohort 1 and 2.
Intervention Type
Biological
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Yervoy, BMS-734016, MDXOIO, MDX-CTLA4
Intervention Description
4 courses of 1mg/kg q3w
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
Opdivo, BMS-936558, MDX1106, ONO-4538
Intervention Description
4 courses of 3mg/kg q3w, followed by maintenance flat dose (480mg, q4w, for 10 doses)
Primary Outcome Measure Information:
Title
Efficacy endpoint: DCR
Description
Disease control rate (DCR) of >6mo; this includes a change from baseline in tumour volume as measured by SD, PR or CR by best ORR in evaluable participants, all lasting longer than 6mo
Time Frame
At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49
Secondary Outcome Measure Information:
Title
Safety endpoint: adverse effects
Description
Percentage of Grade 3/4 and 5 treatment-related adverse effects
Time Frame
At inclusion, Weeks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and at end of treatment (typically at one year, or earlier when treatment is stopped prematurely)
Title
Efficacy endpoint: ORR
Description
Best objective response rate (ORR) per RECIST1.1 criteria
Time Frame
At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49
Title
Efficacy endpoint: BRR
Description
Biochemical response rate (BRR) at week 13 and maximal PSA decline according to PCWG3 criteria
Time Frame
BRR at Week 13, PSA at inclusion, Weeks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment (typically one year, or earlier when treatment is stopped prematurely)
Title
Efficacy endpoint: rPFS
Description
Radiographic progression free survival per irRECIST1.1 immune-related response criteria
Time Frame
At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49
Other Pre-specified Outcome Measures:
Title
Translational endpoint: biomarkers
Description
To further optimize and validate predictive and early response immunogenic signatures from biomarkers in tissue and blood, associating with an objective response and disease control (DCR) of at least 6 months.
Time Frame
Through study completion, an average of 2 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: Written informed consent. Histological diagnosis of adenocarcinoma of the prostate. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma. Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease defined either as measurable disease by RECIST1.1 criteria or presence of bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable disease is compulsory. An immunogenic phenotype, consisting of one of the next criteria: 1, mismatch repair deficiency and/or a high mutational burden of >7 mutations per Mb (cluster A); 2, BRCA2 inactivation or BRCAness signature (cluster B); 3, a tandem duplication signature and/or CDK12 biallelic inactivation (cluster C) Age ≥18 years. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. PSA ≥ 2 ng/ml. Documented willingness to use an effective means of contraception while participating in the study and for 7 months post last dose of treatment Documented ongoing castrate serum testosterone <50 ng/dL (<2.0 nM). Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment. Progression of disease by: PSA utilizing PCWG3 criteria Bone scan: disease progression as defined by at least 2 new lesions on bone scan. Soft tissue disease progression defined by modified RECIST 1.1. Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases. Having a biopsiable metastatic lesion and willingness to undergo a baseline* and on treatment tumour biopsy for next-generation sequencing and biomarker analyses. When sufficient FFPE material is available from a biopsy in castrate-state, one may apply for a waiver for a new baseline biopsy. Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1 antagonists) for cohort 1. For cohort 2, patients may have prior treatment with monotherapy CTLA-4 or PD-1 or PD-L1. Surgery or chemotherapy within 4 weeks prior to trial entry / randomisation into the study. Any other therapies for prostate cancer, other than GnRH analogue therapy and osteoporosis preventing agents, are not allowed. Radiotherapy within 2 weeks prior to trial entry. Radiation-related side effects higher than grade 1, or above baseline. Participation in another interventional clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry/randomisation. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism. Untreated or symptomatic brain or leptomeningeal involvement. Inadequate organ and bone marrow function as evidenced by: hemoglobin <6.2 mmol/L Absolute neutrophil count <1.0 x 109/L Platelet count < 75 x 109/L Albumin <30 g/dL. AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥ 5 x ULN if liver metastases present) Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert's disease) Serum Creatinine > 1.5 x ULN Any of the following cardiac criteria; a. Any clinically significant abnormalities in rhythm conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block) c. Experience of any of the following procedures or conditions in the preceding six months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, congestive heart failure NYHA ≥ Grade2 d. Uncontrolled hypotension defined as systolic blood pressure (BP) <90mmHg and/or diastolic BP <50mmHg Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis. History of clinically relevant auto-immune disease (including Crohn's disease or ulcerative colitis). Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of nivolumab or ipilimumab or that may affect the interpretation of the results or renders the patients at high risk from treatment complications. Need for chronic corticosteroid therapy of >10 mg of prednisolone or >0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase. Malignancies other than prostate cancer within 3 years prior to trial entry / randomization, except for adequately treated basal or squamous cell skin cancer and non-muscle invasive bladder cancer. Active second malignancy, except basal or squamous cell skin cancer and non-muscle invasive bladder cancer. Other treated malignancies with curative intent, including colorectal cancer, may be included following PI consent. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy. Inability to comply with study and follow-up procedures. Patients with predominant small cell or neuroendocrine prostate cancer are not eligible. Patients without measurable lesion per RECIST1.1, and with a superscan on bone scintigraphy not evaluable per PCWG3 criteria, are not eligible
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Niven Mehra, PhD
Phone
+31-24-3610354
Email
niven.mehra@radboudumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Niven Mehra, PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Radboudumc
City
Nijmegen
State/Province
Gelderland
ZIP/Postal Code
6525GA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Niven Mehra, MD, PhD
Phone
+31243610354
Email
niven.mehra@radboudumc.nl
First Name & Middle Initial & Last Name & Degree
Eline Smits
Phone
+31243655388
Email
studies.onco@radboudumc.nl
First Name & Middle Initial & Last Name & Degree
Niven Mehra, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Ipilimumab With Nivolumab for Molecular-selected Patients With Castration-resistant Prostate Cancer

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