Durvalumab and Tremelimumab in Treating Chemotherapy Naive Patients With Metastatic Castration-Resistant Prostate Cancer

A Pilot Trial to Explore the Link Between Immunological Changes, Efficacy, Safety, and Tolerability of Durvalumab (MEDI4736) Plus Tremelimumab in Chemotherapy-Naïve Men With Metastatic Castration-Resistant Prostate Cancer (CRPC)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03204812

Enrollment

Registered

2017-07-02

Start date

2017-07-14

Completion date

2021-04-13

Last updated

2024-10-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Castration-Resistant Prostate Carcinoma, Metastatic Malignant Neoplasm in the Bone, Prostate Adenocarcinoma, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8

Brief summary

This phase II trial studies the safety, tolerability and how well durvalumab and tremelimumab work in treating participants with castration-resistant prostate cancer who have not received chemotherapy (chemotherapy naïve) and has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed description

PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of durvalumab plus tremelimumab in patients with metastatic castration-resistant prostate cancer. SECONDARY OBJECTIVES: I. To assess the efficacy of durvalumab plus tremelimumab in patients with metastatic castration-resistant prostate cancer. II. To explore immunological changes in peripheral blood and tissue (e.g. peripheral blood cluster of differentiation \[CD\] 4+ \[Inducible COStimulator (ICOS)\]+ T cells, CD3 expression in tissue) in response to durvalumab plus tremelimumab in patients with metastatic castration-resistant prostate cancer. OUTLINE: Patients receive tremelimumab intravenously (IV) over 60 minutes and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles for tremelimumab and up to 13 cycles for durvalumab in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30, 60, and 90 days, and then every 3 months thereafter.

Interventions

BIOLOGICALDurvalumab

Given IV

BIOLOGICALTremelimumab

Given IV

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Written informed consent. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Life expectancy of \>= 52 weeks. * Hemoglobin \>= 11.0 g/dL. * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (\> 1500 per mm\^3). * Platelet count \>= 100 x 10\^9/L (\>100,000 per mm\^3). * Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician. * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]/alanine aminotransferase \[ALT\] serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal. * Serum creatinine clearance (CL) \> 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. * Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Consent to MD Anderson laboratory protocol PA13-0291 and LAB02-152. * Willing to have peripheral blood mononuclear cells and bone marrow biopsies to be collected prior to receiving the first dose of durvalumab and tremelimumab, after 2-doses and 4-doses of durvalumab and tremelimumab, after 2nd treatment administration and 4th treatment administration. * Histologically or cytologically confirmed adenocarcinoma of the prostate. * Evidence of metastatic disease to the bone seen on most recent bone scan, computed tomography (CT) scan and/or magnetic resonance imaging (MRI). * Asymptomatic or minimally symptomatic patients (do not require narcotics for prostate cancer-related pain). * Tumor progression while on hormone therapy with castrate levels serum testosterone (=\< 1.7 nmol/L or 50 ng/dL) defined by prostate-specific antigen (PSA) and/or radiographic criteria according to the Prostate Cancer Working Group 3 (PCWG3). Castrate levels of testosterone must be maintained by surgical or medical means throughout the conduct of the study.

Exclusion criteria

* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site), previous enrollment in the present study. * Participation in another clinical study with an investigational product during the last 4 weeks. * Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab. * History of another primary malignancy except for: 1) Malignancy treated with curative intent and with no known active disease \>= 5 years before the first dose of study drug and of low potential risk for recurrence. 2) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3) Adequately treated carcinoma in situ without evidence of disease (e.g., superficial bladder cancer). * Evidence of visceral metastasis to the liver. * Prior use of taxane-based chemotherapy for treatment of castrate resistant prostate cancer. * Receipt of the last dose of anti-cancer therapy (immunotherapy, endocrine therapy \[e.g., abiraterone acetate, enzalutamide\], targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) =\< 28 days prior to the first dose of study drug. (with the exception of any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab.) * Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of durvalumab or tremelimumab. Note: Local surgery of isolated lesions for palliative intent is acceptable. * QT interval corrected for heart rate using Fridericia's formula (QTcF) \>= 470 ms. Any clinically significant abnormalities detected, require triplicate electrocardiogram (ECG) results and a mean QT interval corrected for heart rate using Fridericia's formula (QTcF) \>= 470 ms calculated from 3 electrocardiograms (ECGs). * Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of: intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid or steroids as pre-medication for hypersensitivity reactions (e.g. CT scan premedication). * Any unresolved toxicity (Common Terminology Criteria for Adverse Events \[CTCAE\] grade \>= 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy). * Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia; * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; * Any chronic skin condition that does not require systemic therapy; * Patients without active disease in the last 5 years may be included but only after consultation with the study physician; * Patients with celiac disease controlled by diet alone. * Subjects with history of diverticulitis may be included only after consultation and approval of the study physician. * History of primary immunodeficiency. * History of allogeneic organ transplant. * History of hypersensitivity to the combination of durvalumab and tremelimumab. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diathesis including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent. * Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Known history of positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection. * History of leptomeningeal carcinomatosis. * Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab. * Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. * Brain metastases or spinal cord compression unless asymptomatic or treated and stable off steroids and anti-convulsants for at least 28 days prior to study treatment start. Patients with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. * Subjects with uncontrolled seizures. * Male patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. * A malignancy \[other than the one treated in this study\] which required radiotherapy or systemic treatment within the past 5 years, or has a \>= 30% probability of recurrence within 24 months (except for non-melanoma skin cancer or Ta urothelial carcinomas)

Design outcomes

Primary

Measure	Time frame	Description
Number of Adverse Events	from date of the first treatment, up to 43.6 months	Toxicity will be monitored in all patients who receive at least one dose of tremelimumab, even if the patient is not evaluable for the biomarker or efficacy endpoint. Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03.

Secondary

Measure	Time frame	Description
Prostate-specific Antigen (PSA) Progression Free Survival (PFS)	from the first day of treatment, up to 43.6 months	PSA PFS is defined as per Prostate Cancer Working Group 3 (PCWG3) criteria: time from start of therapy to first PSA increase of 25% and ≥2 ng/mL above the nadir, and which is confirmed by a second value ≥3 weeks later. PSA PFS were calculated from the first day of treatment and summarized by Kaplan-Meier methods.
Radiographic Progressive Free Survival (rPFS)	from first day of treatment, up to 43.6 months	rPFS is measured from first dose to date of disease progression on CT and/or bone scan or death from any cause, whichever occurs first. Radiographic PFS will start at the first day of treatment and will be summarized by Kaplan-Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1),as a 20% increase in the sum of the longest diameter of target lesions, or ameasurable increase in a non-target lesion, or the appearance of new lesions
Number of Participants With PSA Decline of ≥50% From Start of Therapy	baseline, up to 43.6 months	PSA decline will start at the first day of treatment and will be summarized by Kaplan-Meier. The numeric PSA value at maximal decline will be summarized by a boxplot and as a scatter plot of maximal decline by baseline PSA. PSA is produced by normal and cancerous prostate tissue. PSA levels are often elevated in men with prostate cancer.
Median Overall Survival	from start of treatment, up to 43.6 months	Overall Survival is the time which begins at diagnosis (or at the start of treatment) and up to the time of death.

Countries

United States

Participant flow

Recruitment details

Recruitment Details: July 2017- April 2019

Pre-assignment details

31 participants consented, 5 participants were inevaluable.

Participants by arm

Arm	Count
Treatment (Tremelimumab, Durvalumab) Patients receive tremelimumab IV over 60 minutes and durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for up to 4 cycles for tremelimumab and up to 13 cycles for durvalumab in the absence of disease progression or unacceptable toxicity.	26
Total	26

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	3

Baseline characteristics

Characteristic	Treatment (Tremelimumab, Durvalumab)
Age, Continuous	67.5 years
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	2 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	22 Participants
Region of Enrollment United States	26 participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	26 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	14 / 26
other Total, other adverse events	26 / 26
serious Total, serious adverse events	10 / 26

Outcome results

Primary

Number of Adverse Events

Toxicity will be monitored in all patients who receive at least one dose of tremelimumab, even if the patient is not evaluable for the biomarker or efficacy endpoint. Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.03.

Time frame: from date of the first treatment, up to 43.6 months