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Avelumab With Bempegaldesleukin With or Without Talazoparib or Enzalutamide in Advanced or Metastatic Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04052204
Recruitment Status : Terminated (Study prematurely terminated as the experimental treatments evaluated in study B9991040 may not provide additional clinical benefit over current or future Standard of Care in the different therapeutic indications that this trial was to evaluate.)
First Posted : August 9, 2019
Results First Posted : October 14, 2021
Last Update Posted : October 14, 2021
Sponsor:
Collaborators:
EMD Serono
Nektar Therapeutics
Astellas Pharma Inc
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Evaluation of the combination of avelumab + bempegaldesleukin (NKTR-214 ) in locally advanced squamous cell carcinoma of the head and neck ( metastatic SCCHN) and avelumab + bempegaldesleukin (NKTR-214) + talazoparib or enzalutamide in metastatic castration resistant prostate cancer (mCRPC).

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma of the Head and Neck (SCCHN) Metastatic Castration Resistant Prostate Cancer (mCRPC) Drug: avelumab Drug: Bempegaldesleukin Drug: talazoparib Drug: enzalutamide Phase 1 Phase 2

Detailed Description:

Phase 1b/ Phase 2 Design

Phase 1b will be the sequential dose-finding study.

Once the Phase 1b component is completed, Phase 2 will be initiated to further evaluate the safety and anti-tumor activity across combinations of therapy.

Combination A will enroll participants with SCCHN.

Combination B and C will enroll participants with mCRPC

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Combination A: Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck

Combination B: Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will enroll participants with DDR defect positive mCRPC.

Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination With Bempegaldesleukin(NKTR-214) With or Without Talazoparib or Enzalutamide in Participants With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date : December 30, 2019
Actual Primary Completion Date : September 29, 2020
Actual Study Completion Date : September 29, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combination A
Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck
Drug: avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
  • Bavencio
  • MSB0010718C

Drug: Bempegaldesleukin
Investigational CD122-biased cytokine agonist
Other Name: NKTR-214

Experimental: Combination B
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will focus on enrolling participants with DDR defect positive mCRPC.
Drug: avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
  • Bavencio
  • MSB0010718C

Drug: Bempegaldesleukin
Investigational CD122-biased cytokine agonist
Other Name: NKTR-214

Drug: talazoparib
poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor
Other Name: Talzenna

Experimental: Combination C
Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC
Drug: avelumab
Investigational fully human anti-PD-L1 monoclonal antibody
Other Names:
  • Bavencio
  • MSB0010718C

Drug: Bempegaldesleukin
Investigational CD122-biased cytokine agonist
Other Name: NKTR-214

Drug: enzalutamide
androgen receptor inhibitor
Other Name: Xtandi




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLT) [ Time Frame: Cycle 1 of the treatment period (28 days) ]
    DLTs were graded according to NCI- CTCAE version 4.03 and coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) as event category and MedDRA primary system organ class (SOC) body term as Body System category.


Secondary Outcome Measures :
  1. Duration of Response (DR) [ Time Frame: Approximately 8 months (246 days). ]

    DR was defined, for participants with a confirmed Objective Response (OR), as the time from the first documentation of OR to the date of first documentation of progressive disease (PD) or death due to any cause. The documentation of PD was defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If a subject had not had an event (PD or death), DR was censored at the date of last adequate tumor assessment.

    As there were no objective responses in the study, no participant met the definition of analysis population.


  2. Time to Tumor Response (TTR) [ Time Frame: Approximately 8 months (246 days). ]

    TTR was defined, for participants with objective response, as the time from the date of first dose of study treatment to the first documentation of objective response (Complete Response or Partial Response) which was subsequently confirmed.

    As there were no objective responses in the study, no participant met the definition of analysis population.


  3. Progression-Free Survival (PFS) [ Time Frame: Approximately 8 months (246 days). ]
    Progression-Free Survival (PFS) was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurred first. PFS data were censored on the date of the last adequate tumor assessment for participants who did not have an event (PD or death), for participants who started new anti-cancer therapy prior to an event, or for participants with an event after two or more missing tumor assessments. Participants who did not have an adequate baseline tumor assessment or who did not have any adequate post-baseline tumor assessments were censored on the date of first dose of study treatment unless death occurred on or before the time of the second planned tumor assessment, in which case the death was considered an event. PFS time was summarized using the Kaplan-Meier method.

  4. Overall Survival (OS) [ Time Frame: Approximately 8 months (246 days). ]

    Overall survival (OS) was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact.

    OS time was summarized using the Kaplan-Meier method.


  5. Pharmacokinetic (PK) Parameters - Cmax and Ctrough for Avelumab and NKTR-214 [ Time Frame: Blood samples were collected on Day 1 and Day 15 in Cycle 1 and Cycle 2 for avelumab. Blood samples were collected on Day 1, Day 3, Day 4 and Day 8 in Cycle 1, Day1 and Day 8 in Cycle 2 for NKTR-214. ]
    Cmax was defined as the maximum observed plasma concentration at the end of infusion. Ctrough was defined as the predose concentration at the end of dosing interval.

  6. Number of Participants With Positive Anti-Drug Antibody (ADA) Results [ Time Frame: Day 1 of Cycle 1, 2 and end of treatment (EOT). ]
    ADA against avelumab and NKTR-214 in serum samples was determined and reported separately for ADA never-positive, ADA ever-positive participants, baseline ADA positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response. For all participants, blood for ADA samples was drawn from the contralateral arm of the avelumab and NKTR-214 infusion.

  7. Number of Participants With Positive Neutralizing Antibody (nAb) Results [ Time Frame: Day 1 of Cycle 1, 2 and EOT ]
    nAb in serum samples was determined and reported separately for nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.

  8. PD-L1 Expression Level in Baseline and On-treatment Tumor Tissue [ Time Frame: On-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14 for participants in Combination A. ]
    PD-L1 expression level in baseline tumor tissue, and in on-treatment tumor tissue was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and/or inflammatory cells in regions of interest. PD-L1 expression level in baseline tumor tissue and in on-treatment tumor tissue were under pathological analyses, assisted by image analysis. Participants were classified as positive or negative according to scoring algorithms and cut-offs established from internal or external sources.

  9. Number of Participants With Treatment-Emergent Adverse Events(TEAEs), Serious TEAEs, TEAEs Leading to Death and Infusion-Related Reactions (IRRs) During On-treatment Period [ Time Frame: Approximately 6 months (190 days) ]
    Adverse events (AEs) were any untoward medical occurrences in a participant or clinical study participants, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment). A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that, at any dose: a. Results in death, b. Was life-threatening, c. Required inpatient hospitalization or prolongation of existing hospitalization, d. Resulted in persistent disability/incapacity, e. Was a congenital anomaly/birth defect. Causality to study treatment was determined by the investigator.

  10. Number of Participants With Laboratory Abnormalities With NCI-CTCAE Grade >= 3 - Safety Analysis Set [ Time Frame: Day 1, Day 15 of each treatment cycle ]
    Liver Function Tests of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI) were used to assess possible drug induced liver toxicity. The number of participants with at least one of the following laboratory results were summarized below: 1. (ALT ≥3 × ULN or AST ≥3 × ULN) post-baseline. 2. TBILI ≥2 × ULN post-baseline. 3. (ALP ≤2 × ULN or missing) post-baseline.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must be ≥ 18 years old.
  • Participants with SCCHN or mCRCP.
  • Participants must have histological diagnosis of solid tumors and provide tumor tissue.
  • Measurable disease by RECIST v1.1 with at least 1 measurable lesion.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
  • Adequate bone marrow, renal and liver function
  • Highly effective contraceptive use by men with the ability to father a child or women of childbearing potential.
  • A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) at C1D1.
  • Signed and dated informed consent.

Exclusion Criteria:

  • Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monocolonal antibodies.
  • Known history of: immune-mediated colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis.
  • Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
  • Prior organ transplantation including allogenic stem cell transplantation.
  • Vaccination within 4 weeks prior to C1D1 and while on trial is prohibited except for administration of inactivated vaccines.
  • Known symptomatic brain lesions requiring steroids.
  • Known history of testing positive for human immunodeficiency virus (HIV or known acquired immunodeficiency syndrome (AIDS).
  • Positive HBV surface antigen or HCV test indicating acute or chronic infection..
  • Active infection requiring systemic therapy
  • Clinically significant (i.e., active) cardiovascular disease including the following: documented left ventricular ejection fraction (LVEF) <50% by ECHO/MUGA; cerebral vascular accident/stroke or transient ischemic attack; myocardial infarction; unstable angina; congestive heart failure or serious cardiac arrhythmia (uncontrolled, clinically significant) requiring medication.
  • Diagnosis of any other malignancy within 2 years prior to C1D1, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix and for Combination A only, low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (e.g., surgery, radiation, or castration) or adequately treated prostate cancer.
  • Current use of immunosuppressive medication at the time of study enrollment.
  • Major surgery within 4 weeks prior to study enrollment.
  • Conditions that may impair intake or absorption such as inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1.
  • Participation in other studies involving investigational drug(s) within 2 weeks prior to C1D1.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04052204


Locations
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United States, New York
University of Rochester Medical Center
Rochester, New York, United States, 14642
Belgium
GZA Ziekenhuizen campus Sint-Augustinus
Wilrijk, Antwerpen, Belgium, 2610
Poland
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy
Warszawa, Mazowieckie, Poland, 02-781
Spain
Hospital Quirón Barceloma
Barcelona, Spain, 08023
Hospital Universitari Vall d'Hebron
Barcelona, Spain, 08035
Sponsors and Collaborators
Pfizer
EMD Serono
Nektar Therapeutics
Astellas Pharma Inc
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] June 27, 2019
Statistical Analysis Plan  [PDF] September 3, 2019

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT04052204    
Other Study ID Numbers: B9991040
2019-001358-24 ( EudraCT Number )
First Posted: August 9, 2019    Key Record Dates
Results First Posted: October 14, 2021
Last Update Posted: October 14, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Squamous Cell Carcinoma of Head and Neck
Neoplasms by Site
Neoplasms
Carcinoma, Squamous Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Head and Neck Neoplasms
Avelumab
Talazoparib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action