PMID- 34301808
OWN - NLM
STAT- MEDLINE
DCOM- 20220110
LR  - 20240402
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 9
IP  - 7
DP  - 2021 Jul
TI  - CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in 
      patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, 
      dose-finding study.
LID - 10.1136/jitc-2021-002446 [doi]
LID - e002446
AB  - BACKGROUND: Probody(R) therapeutics are antibody prodrugs designed to be activated 
      by tumor-associated proteases. This conditional activation restricts antibody 
      binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. 
      Here, we report the phase 1 data from the first-in-human study of CX-072 
      (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed 
      death-ligand 1 (PD-L1), in combination with the anti-cytotoxic 
      T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab. METHODS: 
      Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death 
      protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy 
      dose-escalation portion of this multicenter, open-label, phase 1/2 study 
      (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 
      design and continued until the maximum tolerated dose (MTD) was determined. 
      Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four 
      cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The 
      primary objective was identification of dose-limiting toxicities and 
      determination of the MTD. Other endpoints included the rate of objective response 
      (Response Evaluation Criteria In Solid Tumors v.1.1). RESULTS: Twenty-seven 
      patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation 
      cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 
      (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose 
      level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 
      colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended 
      phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 
      weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 
      immune-related AEs were reported in nine (33%) and six (22%) patients, 
      respectively. Three patients (11%) discontinued treatment because of AEs. The 
      overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal 
      squamous cell carcinoma) and four partial responses (cancer of unknown primary, 
      leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months 
      in four patients. CONCLUSIONS: The MTD and recommended phase 2 dose of pacmilimab 
      (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable 
      tolerability profile.
CI  - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Sanborn, Rachel E
AU  - Sanborn RE
AUID- ORCID: 0000-0003-0542-6054
AD  - Department of Medical Oncology, Earle A. Chiles Research Institute, Providence 
      Cancer Institute, Portland, Oregon, USA Rachel.Sanborn@providence.org.
FAU - Hamid, Omid
AU  - Hamid O
AD  - Department of Medical Oncology, The Angeles Clinic and Research Institute, A 
      Cedars-Sinai Affiliate, Los Angeles, California, USA.
FAU - de Vries, Elisabeth Ge
AU  - de Vries EG
AD  - Department of Medical Oncology, Universitair Medisch Centrum Groningen, 
      University of Groningen, Groningen, Netherlands.
FAU - Ott, Patrick A
AU  - Ott PA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts, USA.
FAU - Garcia-Corbacho, Javier
AU  - Garcia-Corbacho J
AD  - Department of Medical Oncology, Hospital Clinic Barcelona/IDIBAPS, Barcelona, 
      Spain.
FAU - Boni, Valentina
AU  - Boni V
AD  - Department of Medical Oncology, START Madrid-CIOCC, Hospital Universitario HM 
      Sanchinarro, Madrid, Spain.
FAU - Bendell, Johanna
AU  - Bendell J
AD  - Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee, USA.
FAU - Autio, Karen A
AU  - Autio KA
AD  - Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, 
      New York, USA.
FAU - Cho, Daniel C
AU  - Cho DC
AD  - Department of Medicine, Perlmutter Cancer Center at NYU Langone Medical Center, 
      New York, New York, USA.
FAU - Plummer, Ruth
AU  - Plummer R
AD  - Department of Medical Oncology, Northern Centre for Cancer Care, Newcastle 
      Hospitals NHS Trust and Newcastle University, Newcastle upon Tyne, UK.
FAU - Stroh, Mark
AU  - Stroh M
AD  - CytomX Therapeutics Inc, South San Francisco, California, USA.
FAU - Lu, Lawrence
AU  - Lu L
AD  - CytomX Therapeutics Inc, South San Francisco, California, USA.
FAU - Thistlethwaite, Fiona
AU  - Thistlethwaite F
AD  - Department of Medical Oncology, The Christie Hospital NHS Foundation Trust and 
      University of Manchester, Manchester, UK.
LA  - eng
SI  - ClinicalTrials.gov/NCT03013491
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Ipilimumab)
RN  - 0 (Prodrugs)
SB  - IM
CIN - doi: 10.1136/jitc-2021-002447
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - B7-H1 Antigen/*antagonists & inhibitors/immunology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Immune Checkpoint Inhibitors/administration & dosage
MH  - Immunotherapy
MH  - Ipilimumab/administration & dosage
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*drug therapy/immunology
MH  - Prodrugs/administration & dosage
PMC - PMC8311331
OTO - NOTNLM
OT  - B7-H1 antigen
OT  - CTLA-4 antigen
OT  - immunotherapy
OT  - investigational
OT  - therapies
COIS- Competing interests: RES: Honoraria from Amgen and AstraZeneca. Advisory boards 
      for AstraZeneca, Blueprint Medicines, Celldex, Daiichi Sankyo, EMD Serono, 
      Genentech/Roche, Janssen, and Seagen. Research support from AstraZeneca and 
      Merck. OH: Consulting/advisory boards for Aduro, Akeso, Amgen, Beigene, Bioatla, 
      BMS, Roche Genentech, GSK, lmmunocore, ldera, lncyte, Janssen, Merck, Nextcure, 
      Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, and Zelluna. 
      Speakers' bureau for BMS, Novartis, Pfizer, and Sanofi/Regeneron. Institutional 
      financial support for contracted research from Arcus, Aduro, Akeso, Amgen, 
      Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, lmmunocore, ldera, lncyte, 
      lovance, Merck, Moderna, Merck-Serano, NextCure, Novartis, Pfizer, 
      Sanofi/Regeneron, Seattle Genetics, Torque, and Zelluna. EGEdV: Institutional 
      financial support for clinical trials or contracted research from Amgen, 
      AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics Genentech, Nordic Nanovector, 
      Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial 
      support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and 
      Sanofi; all outside the submitted work. PAO: Research funding from and has 
      advisory role for Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, 
      Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences 
      and Roche/Genentech. JG-C: Speaker's bureau for Bayer; Fees to support 
      registration and attending scientific meetings from BMS, Novartis. VB: 
      Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences; 
      Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial 
      support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, Amgen, 
      Astellas, AstraZeneca, BeiGene, BMS, Boehringer Ingelheim, Boston Therapeutics, 
      CytomX Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, 
      Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Mersana, Nektar, Macrogenics, 
      Menarini, Merck, Merus, Millenium, MSD, Nanobiotix, Novartis, ORCA, Pfizer, 
      PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle 
      Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: 
      Institutional financial support for clinical trials or contracted research from 
      AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, 
      ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle 
      Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, 
      Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD 
      Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech / Roche, 
      Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, 
      Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, 
      Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, 
      Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, 
      Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude 
      Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, 
      Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck 
      Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, 
      TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, 
      Vyriad, and Zymeworks. Institutional financial support for advisory 
      boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, 
      AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum 
      Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, 
      Genentech / Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, 
      Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular 
      Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, 
      Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle 
      Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug 
      Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or 
      travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech / Roche, Gilead, 
      Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: 
      Advisory board for CytomX (unpaid). Institutional financial support for clinical 
      trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, 
      Pfizer, and Tizona. DCC: Consultant for Nektar Therapeutics, GSK, Torque, 
      PureTech, and HUYA. RP: Honoria for attending advisory boards from Pierre Faber, 
      Bayer, Octimet, Clovis Oncology, Novartis, Karus Therapeutics, Biosceptre, BMS, 
      Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapeutics and Sanofi Aventis. Fees 
      for delivery of educational talks or chairing educational meetings by 
      AstraZeneca, Novartis, Bayer, Tesaro and BMS. Funds to support attendance at 
      conferences from BMS and MSD. MS is a former employee and Lawrence Lu is a 
      current employee of CytomX Therapeutics and both own stock in CytomX 
      Therapeutics. FT: Research funding and conference registration from Novartis. 
      Consultancy/advisory role for GSK, Achilles Therapeutics, BMS, Zelluna, Enara 
      Bio, Bayer, T-Knife.
EDAT- 2021/07/25 06:00
MHDA- 2022/01/11 06:00
PMCR- 2021/07/23
CRDT- 2021/07/24 05:40
PHST- 2021/05/02 00:00 [accepted]
PHST- 2021/07/24 05:40 [entrez]
PHST- 2021/07/25 06:00 [pubmed]
PHST- 2022/01/11 06:00 [medline]
PHST- 2021/07/23 00:00 [pmc-release]
AID - jitc-2021-002446 [pii]
AID - 10.1136/jitc-2021-002446 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2021 Jul;9(7):e002446. doi: 10.1136/jitc-2021-002446.