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Clinical Trial
. 2023 Mar;11(3):e005702.
doi: 10.1136/jitc-2022-005702.

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC)

Karen A Autio  1 , Celestia S Higano  2 , Luke Nordquist  3 , Leonard J Appleman  4 , Tian Zhang  5   6 , Xin-Hua Zhu  7 , Hani Babiker  8 , Nicholas J Vogelzang  9 , Sandip M Prasad  10 , Michael T Schweizer  2 , Ravi A Madan  11 , Stephane Billotte  12 , Nora Cavazos  12 , Orlaith Bogg  12 , Ray Li  12 , Kam Chan  12 , Helen Cho  12 , Megan Kaneda  12 , I-Ming Wang  12 , Jenny Zheng  12 , Szu-Yu Tang  12 , Robert Hollingsworth  12 , Kenneth A Kern  12 , Daniel P Petrylak  13
Affiliations
Clinical Trial

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC)

Karen A Autio et al. J Immunother Cancer. 2023 Mar.

Abstract

Background: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).

Methods: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety.

Results: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA.

Conclusions: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT.

Trial registration number: NCT02616185.

Keywords: immunogenicity, vaccine; prostatic neoplasms; therapies, Investigational; vaccination.

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Conflict of interest statement

Competing interests: This work was sponsored by Pfizer. KAA: PI/research funding to institution: Amgen, AstraZeneca, CytomX, Eli Lilly and Company, GlaxoSmithKline, Parker Institute for Cancer Immunotherapy, Pfizer, Trishula. CSH: consulting fees: Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Carrick Therapeutics, Clovis Oncology, Ferring Pharmaceuticals, Genentech, Hinova, Janssen, Menarini, Merck Sharp & Dohme, Myovant Sciences, Novartis, Pfizer; contracted research support: Aragon Pharmaceuticals, Astellas, AstraZeneca, Bayer, Clovis Oncology, eFFECTOR Therapeutics, Emergent BioSolutions, Ferring Pharmaceuticals, Medivation, Roche; ownership interest: CTI BioPharma; honoraria: Astellas. LN and X-HZ: nothing to disclose. LJA: consulting or advisory role: AADi; research funding (institution as recipient): Amgen, Astellas, Aveo, Bayer, BioNTech, Bristol Myers Squibb, Calithera Biosciences, Eisai, Eli Lilly and Company, Epizyme, Exelixis, Genentech/Roche, Inovio, Merck, Novartis, Peloton Therapeutics, Pfizer, Seattle Genetics, Surface Oncology; other relationship: Pfizer; uncompensated relationships: Exelixis. TZ: PI/research funding: AbbVie/StemCentrx, Acerta, Astellas, AstraZeneca, Eli Lilly and Company, Janssen, Merck, Merrimack, Mirati Therapeutics, Novartis, OmniSeq, Personal Genome Diagnostics, Pfizer, Regeneron; speaker: Genomic Health (end 2020), Sanofi-Aventis (end 2020); advisory board/consultant: Amgen, Aptitude Health, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera Biosciences, Clinical Care Options, Dendreon, Eisai, Eli Lilly and Company, Exelixis, Janssen, Merck, MJH Associates, Peerview, Pfizer, Pharmacyclics, QED Therapeutics, Sanofi-Aventis, Seattle Genetics, Vaniam; employee/stockholder: Archimmune Therapeutics (spouse), Capio Biosciences (spouse), Nanorobotics (spouse). HB: consultancy: Caris, Idera, Myovant, Novocure, Tracon; speaker’s bureau: Guardant360. NJV: PI/research funding: none; advisory boards: Caris, Clovis, Eisai, Fujifilm, Gilead Sciences, Merck, OnQuality Pharmaceuticals, Pfizer-Myovant, Sanofi-Aventis, Seagen; speaker’s bureau: Aveo, Bayer, Caris, Janssen, PER, Pfizer-Myovant, Sanofi, Seagen. SMP: PI funding: Janssen, Merck, Pfizer, UroGen Pharma. MTS: paid consultant and/or received honoraria: AstraZeneca, PharmaIn, Resverlogix, Sanofi; research funding to institution: Ambrx, AstraZeneca, Bristol Myers Squibb, F. Hoffman-La Roche, Immunomedics, Janssen, Madison Vaccines, Merck, Pfizer, SignalOne Bio, Tmunity, Zenith Epigenetics. RAM: research funding: Bayer. SB, NC, OB, RL, MK, I-MW, JZ, S-YT, and KAK: employees of Pfizer with stock and/or stock options. KC, HC, and RH: employees of Pfizer at the time of the study. DPP: stock and other ownership interests: Bellicum Pharmaceuticals, TYME Technologies; consulting or advisory role: Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly and Company, Exelixis, Gilead Sciences, Incyte, Ipsen, Janssen, Mirati Therapeutics, Monopteros Therapeutics, Pfizer, Pharmacyclics, Regeneron, Roche, Seattle Genetics, UroGen Pharma; research funding: Advanced Accelerator Applications (Inst), Agensys (Inst), Astellas Medivation (Inst), AstraZeneca (Inst), Bayer (Inst), BioXcel Therapeutics (Inst), Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Eisai (Inst), Endocyte (Inst), Eli Lilly and Company (Inst), Genentech (Inst), Gilead Sciences (Inst), Innocrin Pharma (Inst), MedImmune (Inst), Medivation (Inst), Merck (Inst), Mirati Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Progenics (Inst), Replimune (Inst), Roche (Inst), Sanofi (Inst), Seattle Genetics (Inst); expert testimony: Celgene, Sanofi.

Figures

Figure 1
Figure 1
Study design. The dose for AdC68 was 6×1011 VP if not specified. Post-secondary hormone was defined as a failed androgen receptor-targeted therapy. AdC68, adenovirus vector; BCR, biochemical recurrence; mCRPC, metastatic castration-resistant prostate cancer; pDNA, plasmid DNA; RP2D, recommended phase 2 dose; TRM, tremelimumab; PF-06801591, sasanlimab; VP, viral particles.
Figure 2
Figure 2
Swimmer plot of duration of treatment and tumor response over time per RECIST V.1.1 in patients with mCRPC. (A) Patients with mCRPC excluding Cohorts 7A-mCRPC and 3B-mCRPC. (B) Patients with mCRPC in Cohorts 7A-mCRPC and 3B-mCRPC. mITT population. Treatment of each cohort see the footnote of table 2. Measurable disease at baseline was defined as showing new or progressive metastatic lymph node and/or local recurrence or visceral metastatic disease (with the exception of metastases to the liver) on CT or MRI scans. Duration of treatment was defined as (last dose date−first dose date+1). One patient from Cohort 3B-mCRPC achieved a confirmed CR (CR was 1.5-cm para-aortic lymph node, patient withdrew from study therapy after early Grade 3 diarrhea). CR, complete response; mCRPC, metastatic castration-resistant prostate cancer; mITT, modified intention-to-treat; NE, not evaluated; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
Figure 3
Figure 3
T-cell immune response. (A) Patients with BCR in Cohort 5B. (B) Patients with mCRPC in Cohorts 7A and 3B. (C) Fold changes from baseline of each antigen. Patients with mCRPC in Cohorts 7A-mCRPC and 3B-mCRPC were treated at the RP2D, which was AdC68 6×1011 VP, the DNA booster vaccine, tremelimumab 80 mg, and sasanlimab 300 mg. For patients with BCR in Cohort 5B-BCR, the treatment was AdC68 6×1011 VP, the DNA booster vaccine, tremelimumab 80 mg, and sasanlimab 130 mg.BCR, biochemical recurrence; CR, complete response; EOT, end of treatment; IFN, interferon; mCRPC, metastatic castration-resistant prostate cancer; NE, not evaluated; PBMC, peripheral blood mononuclear cell; PD, progressive disease; PR, partial response; PSA, prostate-specific antigen; PSCA, prostate stem cell antigen; PSMA, prostate-specific membrane antigen; RP2D, recommended phase 2 dose; SD, stable disease; SFC, spot-forming cells; VP, viral particle.
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