TALazoparib and Avelumab as Maintenance Therapy in Platinum-Sensitive Metastatic or Locally Advanced URothelial Carcinoma

NCT04678362

Last updated date
Study Location
Institut de Cancérologie de l'Ouest
Angers, , , France
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Urothelial Carcinoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Patient ≥18 years at the day of consenting to the study

- Provision of informed consent prior to any study specific procedures

- Histologically confirmed diagnosis of urothelial carcinoma of the renal pelvis, ureter (upper urinary tract), bladder or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.

- Documented Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N, M1) not candidate to a curative treatment with surgery or radiotherapy at the start of first-line platinum-based chemotherapy.

- Patient must have completed prior to inclusion a platinum-based (cisplatin or carboplatin) polychemotherapy for at least 4 cycles of chemotherapy (until 6 cycles maximum) and have a stable disease or a partial response (PR) or a complete response (CR) from the chemotherapy according to RECIST 1.1 criteria

- A minimum dose of 55 mg/m² of cisplatin is required in order to count for 1 cycle.

- A minimum dose of carboplatin AUC 4.5 is required in order to count for 1 cycle

- Eligibility based on this criterion will be established locally by the investigator by examining pre and post-chemotherapy radiological assessments (CT/MRI)

- Neoadjuvant or adjuvant chemotherapy is allowed (with a delay of at least 12 months between the last dose of neoadjuvant or adjuvant chemotherapy and the relapse)

- Patient must be enrolled within 8 weeks after the last dose of chemotherapy.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2;

- Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

- Hemoglobin ≥ 10.0 g/dL (patient may have been transfused before inclusion)

- Absolute neutrophil count (ANC) ≥1.5 x 109/L

- Platelet count ≥100 G/l

- Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤2.5 x ULN unless liver metastases are present in which case they must be ≤5x ULN

- Patient must have creatinine clearance estimated using the CKD equation of ≥ 40 mL/min

- Able to swallow and retain oral drug

- Life expectancy > 12 weeks

- Serum pregnancy test (for females of childbearing potential) negative at screening

- Male patient able to father children and female patient of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 60 days after the last dose of treatments

- Patient affiliated to a French Social Security System or a beneficiary of such a system

- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations

- Optional: provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (or subsection thereof) from the most recent primary or metastatic tumor biopsy

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- Patient who has never received chemotherapy with a platinum salt (cisplatin or
carboplatin) for advanced/metastatic urothelial carcinoma


- Patient who has previously received more than one line of chemotherapy for
advanced/metastatic urothelial carcinoma


- Patient whose disease has progressed according to RECIST v1.1 criteria after the first
line platinum-based chemotherapy for urothelial carcinoma. The cancer must not be in
the progression phase at inclusion


- Patient with known CNS metastases and/or carcinomatous meningitis


- Other malignancy within the last 3 years except: adequately treated non-melanoma, skin
cancer curatively treated, in situ cancer of the cervix, ductal carcinoma in situ
(DCIS), localized prostate carcinoma without PSA relapse


- Patient with myelodysplastic syndrome/acute myeloid leukemia history or with features
suggestive of MDS/AML


- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
agent. Patient with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
diseases not requiring immunosuppressive treatment are eligible. Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) are allowed.Current treatment with an
immunosuppressant medicinal product or treatment within 7 days prior to inclusion,
EXCEPT:


- Intra-nasal, inhaled or local steroids or local steroid injections (such as
intra-articular injections)


- Systemic corticosteroids at physiological doses of ≤ 10 mg/day of prednisone or
equivalent


- Steroids as premedication for hypersensitivity reactions (such as CT scan
premedication)


- Major surgery within 4 weeks or major radiotherapy within to starting experimental
treatment. Previous palliative radiotherapy (≤ 10 fractions) for metastatic lesions is
permitted provided that this has been completed at least one week prior to starting
Talazoparib and Avelumab


- Active viral infection (HIV, Hepatitis B/C) or known history of positive test for HIV


- Any previous treatment with PARP inhibitor or any immunotherapy (e.g. anti-CTLA-4 or
anti-PDL1/ PD1)


- Concomitant treatment with any drug on the prohibited medication list such as live
vaccines, concomitant use of strong P-gp inhibitors (cf section "Prohibited
concomitant treatments") or systemic corticoids at dose > 10 mg/day prednisone or
equivalent. Live vaccines administered more than 30 days before study entry are
permitted


- Clinically significant (e.g. active) cardiovascular disease cerebral vascular
accident/stroke in the 3 months prior to enrollment: myocardial infarction,
severe/unstable angina, symptomatic congestive heart failure (≥ New York Heart
Association Classification Class II), serious cardiac arrhythmia requiring medication,
uncontrolled high blood pressure, cerebrovascular accident, transient ischaemic attack


- Patient considered at poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled
major seizure disorder, unstable spinal cord compression, superior vena cava syndrome,
extensive interstitial bilateral lung disease or any psychiatric disorder that
prohibits obtaining informed consent


- Pulmonary embolism or deep vein thrombosis within 3 months prior to inclusion (unless
if stable, asymptomatic and treated with a low molecular heparin for at least 10 days
prior to starting Talazoparib + Avelumab).


- Pregnant or lactating woman;


- Participation in another interventional study with a systemic anti-cancer treatment
within 4 weeks prior to inclusion. Inclusion in observational or interventional
studies not involving a health product is permitted. Patient with telephone follow up
of toxicities and simple laboratory monitoring or other questionnaires alone may be
included.


- Patient unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication;Previous organ transplant including stem cell allotransplantation or double
umbilical cord blood transplantation.


- Patient with a known hypersensitivity to Talazoparib and Avelumab or any of the
excipients of the product.


- People who are vulnerable under the law (minors, adults under legal protection, people
deprived of their freedom)


- Other persisting toxicities related to previous anticancer treatments: "Persisting
toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory
neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on
investigator's judgment are acceptable."

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Advanced Information
Descriptive Information
Brief Title  ICMJE TALazoparib and Avelumab as Maintenance Therapy in Platinum-Sensitive Metastatic or Locally Advanced URothelial Carcinoma
Official Title  ICMJE TALazoparib and Avelumab as Maintenance Therapy in Platinum-Sensitive Metastatic or Locally Advanced URothelial Carcinoma: A Single-arm Phase 2 Trial
Brief Summary The main objectif is to determine the efficacy of a maintenance treatment combining Talazoparib and Avelumab after platinum-based chemotherapy in patients with locally advanced/metastatic urothelial carcinoma.
Detailed Description

The first line treatment of urothelial carcinoma is a platinum-based chemotherapy. This treatment is efficient with a response rate > 50 % but the progression-free survival is short (7.7 months) and the chemotherapy is too toxic to be used in a prolonged time. Traditionally, maintenance chemotherapy refers to the utilization of regimens with less toxicity after the initial upfront treatment. This concept has already been efficient with PARP inhibitors in ovarian carcinoma and more recently with durvalumab in lung carcinoma.

The prevalence of somatic mutations in homologous recombination genes in UC as well as their association with platinum sensitivity suggests Talazoparib to be a target for a maintenance treatment of urothelial carcinoma. Moreover, there is a strong rational with both pre-clinical and clinical data to associate Avelumab and Talazoparib. This appears all the more relevant that Avelumab has already demonstrated its efficacy in urothelial carcinoma (after platinum-based chemotherapy failure).

In this context, the sponsorpropose a phase 2 study to assess the antitumor activity of the combination of Avelumab plus Talazoparib in metastatic urothelial carcinoma in maintenance therapy after platinum-based chemotherapy.

Considering the doubts about the best molecular predictive factors of Talazoparib and Avelumab, the sponsor willingly propose a non-selective study, without molecular screening. Tumors will be selected according to the platinum sensitivity which has the advantage to exclude poor prognosis tumors and will allow increasing the HRD tumor population.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Single-arm phase 2 trial
Masking: None (Open Label)
Masking Description:
None (open label=)
Primary Purpose: Treatment
Condition  ICMJE Urothelial Carcinoma
Intervention  ICMJE Drug: Talazoparib + Avelumab
Patients will receive the combined treatment until the investigator considers that the patient no longer obtains benefit from it. The treatment will be continued until disease progression, unacceptable toxicity or discontinuation for any cause.
Study Arms  ICMJE Experimental: Talazoparib+avelumab
  • Talazoparib will be administered at the daily dose of 1 mg given orally in a 28-day cycle, except for patients with mild renal impairment (Creatinine clearance 30-59 mL/min) who will receive 0.75 mg per day.
  • Avelumab will be administered by intravenous (I.V.) route over 60 minutes at the dose of 800 mg on D1 and D15, in a 28-day cycle.
Intervention: Drug: Talazoparib + Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: December 16, 2020)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient ?18 years at the day of consenting to the study
  • Provision of informed consent prior to any study specific procedures
  • Histologically confirmed diagnosis of urothelial carcinoma of the renal pelvis, ureter (upper urinary tract), bladder or urethra. Both transitional cell and mixed transitional/non-transitional cell histologies are allowed, but transitional cell carcinoma must be the predominant histology.
  • Documented Stage IV disease (T4b, N0, M0; any T, N1-N3, M0; any T, any N, M1) not candidate to a curative treatment with surgery or radiotherapy at the start of first-line platinum-based chemotherapy.
  • Patient must have completed prior to inclusion a platinum-based (cisplatin or carboplatin) polychemotherapy for at least 4 cycles of chemotherapy (until 6 cycles maximum) and have a stable disease or a partial response (PR) or a complete response (CR) from the chemotherapy according to RECIST 1.1 criteria

    • A minimum dose of 55 mg/m² of cisplatin is required in order to count for 1 cycle.
  • A minimum dose of carboplatin AUC 4.5 is required in order to count for 1 cycle
  • Eligibility based on this criterion will be established locally by the investigator by examining pre and post-chemotherapy radiological assessments (CT/MRI)
  • Neoadjuvant or adjuvant chemotherapy is allowed (with a delay of at least 12 months between the last dose of neoadjuvant or adjuvant chemotherapy and the relapse)
  • Patient must be enrolled within 8 weeks after the last dose of chemotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status ? 2;
  • Normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
  • Hemoglobin ? 10.0 g/dL (patient may have been transfused before inclusion)
  • Absolute neutrophil count (ANC) ?1.5 x 109/L
  • Platelet count ?100 G/l
  • Total bilirubin ?1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ?2.5 x ULN unless liver metastases are present in which case they must be ?5x ULN
  • Patient must have creatinine clearance estimated using the CKD equation of ? 40 mL/min
  • Able to swallow and retain oral drug
  • Life expectancy > 12 weeks
  • Serum pregnancy test (for females of childbearing potential) negative at screening
  • Male patient able to father children and female patient of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 60 days after the last dose of treatments
  • Patient affiliated to a French Social Security System or a beneficiary of such a system
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
  • Optional: provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block (or subsection thereof) from the most recent primary or metastatic tumor biopsy

Exclusion Criteria:

  • Patient who has never received chemotherapy with a platinum salt (cisplatin or carboplatin) for advanced/metastatic urothelial carcinoma
  • Patient who has previously received more than one line of chemotherapy for advanced/metastatic urothelial carcinoma
  • Patient whose disease has progressed according to RECIST v1.1 criteria after the first line platinum-based chemotherapy for urothelial carcinoma. The cancer must not be in the progression phase at inclusion
  • Patient with known CNS metastases and/or carcinomatous meningitis
  • Other malignancy within the last 3 years except: adequately treated non-melanoma, skin cancer curatively treated, in situ cancer of the cervix, ductal carcinoma in situ (DCIS), localized prostate carcinoma without PSA relapse
  • Patient with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML
  • Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patient with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) are allowed.Current treatment with an immunosuppressant medicinal product or treatment within 7 days prior to inclusion, EXCEPT:

    • Intra-nasal, inhaled or local steroids or local steroid injections (such as intra-articular injections)
    • Systemic corticosteroids at physiological doses of ? 10 mg/day of prednisone or equivalent
    • Steroids as premedication for hypersensitivity reactions (such as CT scan premedication)
  • Major surgery within 4 weeks or major radiotherapy within to starting experimental treatment. Previous palliative radiotherapy (? 10 fractions) for metastatic lesions is permitted provided that this has been completed at least one week prior to starting Talazoparib and Avelumab
  • Active viral infection (HIV, Hepatitis B/C) or known history of positive test for HIV
  • Any previous treatment with PARP inhibitor or any immunotherapy (e.g. anti-CTLA-4 or anti-PDL1/ PD1)
  • Concomitant treatment with any drug on the prohibited medication list such as live vaccines, concomitant use of strong P-gp inhibitors (cf section "Prohibited concomitant treatments") or systemic corticoids at dose > 10 mg/day prednisone or equivalent. Live vaccines administered more than 30 days before study entry are permitted
  • Clinically significant (e.g. active) cardiovascular disease cerebral vascular accident/stroke in the 3 months prior to enrollment: myocardial infarction, severe/unstable angina, symptomatic congestive heart failure (? New York Heart Association Classification Class II), serious cardiac arrhythmia requiring medication, uncontrolled high blood pressure, cerebrovascular accident, transient ischaemic attack
  • Patient considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease or any psychiatric disorder that prohibits obtaining informed consent
  • Pulmonary embolism or deep vein thrombosis within 3 months prior to inclusion (unless if stable, asymptomatic and treated with a low molecular heparin for at least 10 days prior to starting Talazoparib + Avelumab).
  • Pregnant or lactating woman;
  • Participation in another interventional study with a systemic anti-cancer treatment within 4 weeks prior to inclusion. Inclusion in observational or interventional studies not involving a health product is permitted. Patient with telephone follow up of toxicities and simple laboratory monitoring or other questionnaires alone may be included.
  • Patient unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication;Previous organ transplant including stem cell allotransplantation or double umbilical cord blood transplantation.
  • Patient with a known hypersensitivity to Talazoparib and Avelumab or any of the excipients of the product.
  • People who are vulnerable under the law (minors, adults under legal protection, people deprived of their freedom)
  • Other persisting toxicities related to previous anticancer treatments: "Persisting toxicity related to prior therapy (NCI CTCAE Grade > 1); however, alopecia, sensory neuropathy Grade ? 2, or other Grade ? 2 not constituting a safety risk based on investigator's judgment are acceptable."
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04678362
Other Study ID Numbers  ICMJE 2020-001105-24
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party Centre Francois Baclesse
Study Sponsor  ICMJE Centre Francois Baclesse
Collaborators  ICMJE Pfizer
Investigators  ICMJE Not Provided
PRS Account Centre Francois Baclesse
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP