Talazoparib Plus Enzalutamide After Progression to Prior ARPi in Metastatic Prostate Cancer (TEAM PC)
A Multicenter, Open Label, Randomized Phase II Trial to Evaluate the Efficacy of Talazoparib Plus Enzalutamide as First Line Treatment for Patients With Metastatic Castration Resistant Prostate Cancer After Progression to an Androgen Receptor Pathway Inhibitor
The purpose of this clinical trial is to determine the anti-tumor activity of talazoparib plus enzalutamide as first line treatment for metastatic castration resistant prostate cancer (mCRPC) in participants whose disease has progressed on Androgen Receptor Pathway Inhibitor (ARPI).
The main questions it aims to answer are:
- Does talazoparib plus enzalutamide improve efficacy in metastatic castration resistant prostate cancer (mCRPC) compared to enzalutamide alone?
- What is the time to disease progression [radiographic, Prostate Specific Antigen (PSA), clinical] in participants treated with talazoparib plus enzalutamide after progression on abiraterone?
- What medical problems do participants have when receiving talazoparib plus enzalutamide?
Researchers will compare the combination of talazoparib and enzalutamide as a first-line treatment for mCRPC to see if the combination improves the PSA response rate and delays progression compared to enzalutamide alone. The safety and tolerability of the combination (talazoparib and enzalutamide) will also be studied
調査の概要
詳細な説明
This is a multicenter, open-label, randomized, phase II trial to evaluate the efficacy of the combination of talazoparib plus enzalutamide versus enzalutamide as first line treatment for metastatic castration resistant prostate cancer (mCRPC) in participants whose disease has progressed to abiraterone or other androgen receptor inhibitors (ARi) based treatment for metastatic hormone sensitive prostate cancer (mHSPC). Participants who meet the eligibility criteria will be randomized 2:1 to the experimental arm (enzalutamide and talazoparib) or control arm (enzalutamide) and will receive treatment until disease progression, unacceptable toxicity, death or discontinuation from the study treatment for any other reason.
The experimental arm will be evaluated as 2 separate arms, post-AA and post-ARi, each with a single-stage phase II trial design. The control arm will not be directly compared to the experimental arm but will be used to explore biomarker differences in outcome measures between the experimental and control arm and confirm the statistical assumptions for the response rate under the null hypothesis.
Prostate cancer is the second most common malignancy in men worldwide with an estimated annual global incidence of 1.3 million and over 375,000 deaths. Aggressive variant prostate cancer is a clinically defined subset of metastatic castration resistant prostate cancers (mCRPC) characterized by the absence of response to androgen receptor (AR) targeted agents and neuroendocrine features. The treatments that are currently available are not effective, representing an unmet clinical need. The combination of talazoparib, a potent selective PARP inhibitor (PARPi) and enzalutamide (androgen receptor signaling inhibitor; ARPi) demonstrated in the TALAPRO-2 study improved efficacy in metastatic castration resistant prostate cancer (mCRPC) participants with and without DNA damage response (DDR) gene alterations as first line treatment (1L) compared to enzalutamide alone.
Estimated duration of the study: 48 months. Accrual is expected to be completed in 30 months. Median treatment duration has been estimated in 10 months. After completion of (or discontinuation from) treatment, participants will be followed up for survival until end of study (EoS) that will occur at 18 months after the enrollment of the last patient included in the trial, unless premature termination of the study.
It is hypothesized that after progression to abiraterone, the addition of talazoparib to enzalutamide as 1L for mCRPC will result in improved PSA response rate and delayed progression compared to enzalutamide alone.
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Luis Gonzaga Paz-Ares Rodríguez
- 電話番号：+34 91 560 82 27
- メール：info@oncosur.org
研究連絡先のバックアップ
- 名前：Elena Castro, Dra.
- 電話番号：+34 91 560 82 27
- メール：ecastro.imas12@h12o.es
研究場所
-
-
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Madrid、スペイン
- まだ募集していません
- Hospital Fundación Jiménez Díaz
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コンタクト：
- Imanol Martínez Salas
-
-
Barcelona
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Badalona、Barcelona、スペイン、08916
- 募集
- Institut Català d'Oncologia (ICO)
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コンタクト：
- María Ochoa de Olza
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Barcelona、Barcelona、スペイン、08003
- 募集
- Hospital del Mar
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コンタクト：
- Alejo Rodriguez-Vida, Dr.
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Barcelona、Barcelona、スペイン、08036
- 募集
- Hospital Clínico y Provincial de Barcelona
-
コンタクト：
- Begoña Mellado, Dra.
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Sabadell、Barcelona、スペイン、08208
- 募集
- Consorcio Corporación Sanitaria Parc Taulí
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コンタクト：
- Enrique Gallardo, Dr.
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Cantabria
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Santander、Cantabria、スペイン、39008
- 募集
- Hospital Universitario Marqués de Valdecilla
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コンタクト：
- Ignacio Duran, Dr.
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Cádiz
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Cadiz、Cádiz、スペイン、11407
- 引きこもった
- Hospital Universitario de Jerez de la Frontera
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Madrid
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Madrid、Madrid、スペイン、28046
- 募集
- Hospital Universitario La Paz
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コンタクト：
- Estefania Linares, Dra.
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Madrid、Madrid、スペイン、28041
- 募集
- Hospital 12 de Octubre
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コンタクト：
- Elena Castro, Dra.
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Madrid、Madrid、スペイン、28040
- 引きこもった
- Hospital Clínico San Carlos
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Málaga
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Málaga、Málaga、スペイン、29010
- 募集
- Hospital Universitario Virgen de la Victoria
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コンタクト：
- Bernardo Herrera, Dr.
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Vizcaya
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Barakaldo、Vizcaya、スペイン、48903
- 募集
- Hospital Universitario Cruces
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コンタクト：
- Eneko Novo Sukia, Dr.
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Zaragoza
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Zaragoza、Zaragoza、スペイン、50009,
- 募集
- Hospital Universitario Miguel Servet
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コンタクト：
- Ángel Borque, Dr.
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-
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Bordeaux、フランス
- 募集
- Institut Bergonié
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コンタクト：
- Guilhem Roubaud
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Brest、フランス
- 募集
- Hôpital Universitaire de Brest
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コンタクト：
- Benjamin Auberger
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Lille、フランス
- まだ募集していません
- Centre Oscar Lambret
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コンタクト：
- Yaovi Eric Amela
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Paris、フランス
- 募集
- Hôpital Saint Joseph
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コンタクト：
- Carole Helissey
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Strasbourg、フランス
- 募集
- Hôpitaux Universitaire de Strasbourg
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コンタクト：
- Philippe Barthelemy
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Villejuif、フランス
- 募集
- Institut Gustave Roussy
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コンタクト：
- Anna Patrikidou
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Male age 18 or older.
- Histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation or small cell features.
- Willing and able to provide written informed consent to participate in the study. Written consent must be given before registration, according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) / Good clinical practice (GCP), and national/local regulations.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Willing to provide tumor biopsies during the study. Note: At study entry, the pre-treatment new tumor biopsy (fresh-frozen and Formalin-fixed and paraffin-embedded (FFPE) material) could be replaced by an archived tumor biopsy upon agreement from the study chief investigator if such biopsy has been taken after progression to metastatic castration resistance and has both archived fresh-frozen material and a FFPE block with a minimum tumor content over 30 percent. Still the patient must be amenable and willing to undergo a new mandatory post-treatment biopsy.
- Willing to provide blood samples for biomarker analysis.
- Willing to give consent to sequencing of DNA damage repair (DDR) genes for analysis of the prevalence of somatic and germline aberrations in DNA damage repair genes.
- Metastatic (M1) prostate cancer documented by bone scan, or soft tissue disease documented by computed tomography (CT), or magnetic resonance imaging (MRI).
- Asymptomatic or minimally symptomatic prostate cancer at screening.
- Estimated life expectancy of greater than or equal to 6 months from screening.
- Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for participants who have not undergone bilateral orchiectomy must be in place before screening and must continue throughout the study.
12 .Disease progression after at least 12 weeks of treatment with a prior androgen-receptor signalling inhibitor (ARPi), including abiraterone acetate or a direct AR inhibitor, such as enzalutamide, apalutamide, or darolutamide, for metastatic hormone-sensitive prostate cancer. Note: Patients who previously received Enzalutamide can be recruited but up to a maximum of 6. Those patients will be included directly into the experimental arm. Progression is defined as:
a. PSA rise of greater than or equal to 25 percent and an absolute increase of greater than or equal to 2 ng/mL above nadir (or baseline for participants with no PSA decline), confirmed by a second PSA value at least 3 weeks later.
and / or b. Limited radiographic progression: maximum of 2 new bone metastases, no new soft tissue metastasis and less than 50 percent increase in the size of measurable soft tissue lesions.
13. Participants who have received prior docetaxel must meet the following criteria:
a. Received a maximum of 6 cycles of docetaxel for mHSPC and b. Received the last dose of docetaxel equal or higher than 6 months prior to randomization.
14. Participants who have received prior Lu177-PSMA must meet the following criteria:
a. Received a maximum of 6 cycles of docetaxel for mHSPC. b. Received the last dose of Lu177-PSMA equal or higher than 6 months prior to randomization 15. Adequate organ function within 28 days before the first study treatment on Day 1, defined by the following:
-
Haemoglobin greater than or equal to 10 g/dL, no blood transfusions within 14 days before obtaining the haematology laboratory tests at screening,
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Platelets greater than or equal to 100,000/μL no platelets transfusions within 14 days before obtaining the haematology laboratory tests at screening,
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Neutrophils greater than or equal to 1500/μL, no growth factors given within 14 days before obtaining the haematology laboratory tests at screening,
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Serum creatinine less than1.5X ULN or calculated creatinine clearance greater than or equal to 50 mL/min
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Albumin greater than 3 g/dL,
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AST or ALT less than 2.5 × ULN (less than 5 × ULN if liver function abnormalities are due to hepatic metastasis).
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Total serum bilirubin less than 1.5 × ULN (less than 3 × ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation). 16. Ability to swallow study medication tablets and comply with study requirements.
17. Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant, starting contraception at screening and continue throughout the study period and for 3 months after the final treatment administration, (during the treatment period and for at least 90 days after last dose of enzalutamide or at least 120 days after las dose of talazoparib, whichever occurs later) unless the patient is unable to maintain intercourse due to the androgen deprivation.
18. Subjects must not donate sperm starting at screening and throughout the study period and for 3 months after the final abiraterone acetate administration.
19. Subject agrees not to participate in another interventional study while with experimental medical products or anticancer drugs not approved in this setting on treatment in this study. Exceptions could be allowed for protocols investigating the survival or quality of life impact of common routine or conventional drugs (i.e. acetylsalicylic acid, statins, oral antidiabetic drugs) as long as they do not intefere with the study treatment and the evaluation of the main study arms.
20. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria:
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Prior ARPi treatment for less than 12 weeks or disease progression (either PSA or radiographic progression) within 6 months of starting abiraterone or ARi.
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Known or suspected brain metastasis or active leptomeningeal disease.
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Symptomatic or impending spinal cord compression or cauda equina syndrome.
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Use of opiate analgesia for pain from prostate cancer with average Brief pain inventory (BPI) questionnaire score higher than or equal to 6 and/or uncontrolled prostate cancer-related pain requiring increasing doses of opiates within 4 weeks prior to randomization
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Prior treatment with more than one ARPi. This will include abiraterone, enzalutamide, apalutamide, or darolutamide, which are treatments with demonstrated PFS and/or OS benefit in mHPSC, as well as any other novel AR or androgen synthesis directed therapy (with the exception on LHRH/GnRH analogues and/or antagonists). Note: Patients who started on one ARPi and switched to another due to toxicity will only be eligible after prior discussion with the study chair, provided that they were on the first ARPi (other than enzalutamide) for a very limited period of time and can document that they were responding - without PSA rise or worsening symptoms - at the moment they were switched to the second ARPi. Inclusion of such cases will require written notification and approval from the study chair or co-chair.
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Therapeutic radiation therapy within, 14 days (7 days for limited-field palliative radiotherapy) prior to study enrolment, or participants who have not recovered from radiotherapy-related toxicities to grade less than or equal to 1 according to NCI-CTCAE v.5.0.
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Major surgery within 4 weeks prior to randomization or participants who have not recovered from the side effects of any major surgery.
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Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 30 days of Cycle 1 Day 1 or currently enrolled in an investigational study.
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History of seizure or any condition that may predispose to seizure (i.e., prior significant brain trauma, brain vascular malformation, etc) or subjects that have had an unexplained loss of consciousness or transient ischemic attacks within 1 year previous to scheduled day 1 of treatment.
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Congenital long QT syndrome or ECG at screening with QT interval corrected using Fridericia's formula (QTcF) greater than 500 milliseconds.
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Participants with clinically significant cardiovascular disease including but not limited to any of the following:
- Stroke, transient ischemic attack, unstable angina pectoris or documented myocardial infarction within 12 months prior to study entry.
- Symptomatic pericarditis or clinically significant pericardial effusion or myocarditis
- Documented congestive heart failure (New York Heart Association Class, NYHA functional classification III-IV)
- Uncontrolled, persistent hypertension defined as systolic blood pressure greater than 170mmHg or diastolic blood pressure greater than100mmHg. Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
-
Participants with any of the following cardiac conduction abnormalities:
- Ventricular arrhythmias except for benign premature ventricular contractions
- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication.
- Conduction abnormality requiring a pacemaker.
- Other cardiac arrhythmia not controlled with medication.
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Any clinically significant gastrointestinal disorder affecting absorption (i.e., extensive small bowel resection, active inflammatory bowel disease).
-
Active or symptomatic viral hepatitis or chronic liver disease.
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Known/possible hypersensitivity, allergies to enzalutamide, talazoparib or any of capsule excipients.
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Other malignancy except:
- Carcinoma in situ or non-melanoma skin cancer.
- A cancer diagnosed and treated greater than or equal to 5 years before randomization with no subsequent evidence of recurrence.
-
Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject's participation in this study.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
アクティブコンパレータ：Control
Enzalutamide 160 mg orally daily continuously in 28-day cycles. |
Enzalutamide capsules 160 mg orally daily |
|
実験的：Enzalutamide and Talazoparib. Post-AA/ARi according to prior treatment.
Enzalutamide 160 mg and Talazoparib 0.5 mg both orally daily and continuously in 28-day cycles. Note: Patients who previously received Enzalutamide will be included directly into the investigational arm. (Up to a maximum of 6). |
Enzalutamide capsules 160 mg plus talazoparib capsules 0.5 mg, both orally daily |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
PSA response (PSA50)
時間枠：within the first 16 weeks
|
Percentage of participants with a PSA decline greater than or equal to 50 percent from baseline confirmed by a consecutive PSA value (taken at least 3 weeks apart), prior to PSA progression |
within the first 16 weeks
|
|
Objective response rate (ORR)
時間枠：during the first 16 weeks
|
Defined as the best overall radiographic response (partial or complete) during the first 16 weeks on follow up as per investigator assessment of soft tissue/visceral disease per RECIST 1.1 in subjects who have a measurable tumour and/or Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases |
during the first 16 weeks
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Radiographic Progression Free Survival (rPFS)
時間枠：Through study completion, an average of 2 years
|
Time from randomization to first objective evidence of radiographic progression, based on RECIST 1.1 for soft tissue/visceral disease and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines for bone metastases, or death, whichever occurs first. |
Through study completion, an average of 2 years
|
|
Time to PSA Progression (TTPP)
時間枠：Through study completion, an average of 2 years
|
Time from randomization to PSA progression defined as PSA greater than or equal to 25 percent and greater than or equal to 2ng/mL from nadir (or baseline for participants with no PSA decline), confirmed by a second value obtained 3 or more weeks apart as per PCWG3 guidelines. |
Through study completion, an average of 2 years
|
|
Time to unequivocal clinical progression (TTCP)
時間枠：Through study completion, an average of 2 years
|
Time from randomization to clinical worsening of prostate cancer related symptoms, as new onset cancer pain requiring chronic administration of opiate analgesia, deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to 3 or higher, time to first skeletal-related event (the time from randomization to first incidence of radiotherapy to the bone or bone surgery, pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain); or initiation of subsequent lines of active treatment including cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications or symptoms related to disease progression. |
Through study completion, an average of 2 years
|
|
Progression Free Survival (PFS)
時間枠：Through study completion, an average of 2 years
|
Time from randomization to PSA progression, unequivocal clinical progression or radiographic progression, whichever occurs first. |
Through study completion, an average of 2 years
|
|
Incidence of adverse events (AEs)
時間枠：Through study completion, an average of 2 years
|
Total, grouped by grades and AEs category, related and unrelated with the trial treatment. The AEs Defined as incidence of prespecified AEs as per National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, change from baseline in targeted vital signs and change from baseline in targeted clinical laboratory test results. |
Through study completion, an average of 2 years
|
|
Incidence of serious adverse events (SAEs)
時間枠：Through study completion, an average of 2 years
|
Number of Serious Adverse Events, related and unrelated. SAEs leading to treatment discontinuation. |
Through study completion, an average of 2 years
|
|
Drug compliance
時間枠：Through study completion, an average of 2 years
|
Percentage of dose taken for each treatment drug, dose reductions, dose discontinuation (temporary or permanent) |
Through study completion, an average of 2 years
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Assessment of PSA response rate
時間枠：Through study completion, an average of 2 years
|
In participants with and without germline and/or somatic DDR alterations. |
Through study completion, an average of 2 years
|
|
Assessment of ORR
時間枠：Through study completion, an average of 2 years
|
In participants with and without germline and/or somatic DDR alterations |
Through study completion, an average of 2 years
|
|
Assessment of rPFS
時間枠：Through study completion, an average of 2 years
|
In participants with and without germline and/or somatic DDR alterations |
Through study completion, an average of 2 years
|
|
Assessment of TTPP
時間枠：Through study completion, an average of 2 years
|
In participants with and without germline and/or somatic DDR alterations. |
Through study completion, an average of 2 years
|
|
Assessment of TTCP
時間枠：Through study completion, an average of 2 years
|
In participants with and without germline and/or somatic DDR alterations. |
Through study completion, an average of 2 years
|
|
Changes in expression levels of AR in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Changes in expression levels of AR in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Changes in expression of AR-related genes in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Changes in expression of AR-related genes in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Changes in open chromatin regions in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Changes in open chromatin regions in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Survival signaling in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Survival signaling in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
DNA-damage in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
DNA-damage in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Deficient/proficient DNA-repair in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Deficient/proficient DNA-repair in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Other biomarkers in tissue
時間枠：Through study completion, an average of 2 years
|
Changes from tissue samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
|
Other biomarkers in plasma
時間枠：Through study completion, an average of 2 years
|
Changes from plasma samples, studying the correlation of these changes with clinical activity |
Through study completion, an average of 2 years
|
協力者と研究者
スポンサー
捜査官
- 主任研究者：Elena Castro, Dra.、Hospital 12 de Octubre
- スタディチェア：David Olmos, Dr.、Hospital 12 de Octubre
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- TEAM PC_FOS06/2023
- 2023-510536-37-00 (Ctis)
- 2023 (米国 NIH グラント/契約)
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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