PMID- 36066618
OWN - NLM
STAT- MEDLINE
DCOM- 20220916
LR  - 20220925
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 90
IP  - 4
DP  - 2022 Oct
TI  - Model-informed approach for risk management of bleeding toxicities for bintrafusp 
      alfa, a bifunctional fusion protein targeting TGF-beta and PD-L1.
PG  - 369-379
LID - 10.1007/s00280-022-04468-6 [doi]
AB  - PURPOSE: Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the 
      extracellular domain of the transforming growth factor-beta (TGF-beta) receptor II 
      fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 
      (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 
      efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming 
      continuous inhibition of PD-L1 and TGF-beta is required. Here, we describe a 
      model-informed dose modification approach for risk management of BA-associated 
      bleeding adverse events (AEs). METHODS: The PK and AE data from studies 
      NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. 
      Logistic regression analyses were conducted to evaluate potential relationships 
      between bleeding AEs and BA time-averaged concentration (C(avg)), derived using a 
      population PK model. The percentage of patients with trough concentrations 
      associated with PD-L1 or TGF-beta inhibition across various dosing regimens was 
      derived. RESULTS: The probability of bleeding AEs increased with increasing 
      C(avg); 50% dose reduction was chosen based on the integration of modeling and 
      clinical considerations. The resulting AE management guidance to investigators 
      regarding temporary or permanent treatment discontinuation was further refined 
      with recommendations on restarting at RP2D or at 50% dose, depending on the grade 
      and type of bleeding (tumoral versus nontumoral) and investigator assessment of 
      risk of additional bleeding. CONCLUSION: A pragmatic model-informed approach for 
      management of bleeding AEs was implemented in ongoing clinical trials of BA. This 
      approach is expected to improve benefit-risk profile; however, its effectiveness 
      will need to be evaluated based on safety data generated after implementation.
CI  - (c) 2022. The Author(s).
FAU - Vugmeyster, Yulia
AU  - Vugmeyster Y
AUID- ORCID: 0000-0002-6289-2521
AD  - EMD Serono Research and Development Institute, Inc., An Affiliate of Merck KGaA, 
      45 Middlesex Turnpike, Billerica, MA, 01821, USA. yulia.vugmeyster@emdserono.com.
FAU - Grisic, Ana-Marija
AU  - Grisic AM
AD  - Merck Healthcare KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
FAU - Wilkins, Justin J
AU  - Wilkins JJ
AD  - Occams, Amstelveen, The Netherlands.
FAU - Loos, Anja H
AU  - Loos AH
AD  - Merck Healthcare KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
FAU - Hallwachs, Roland
AU  - Hallwachs R
AD  - Merck Healthcare KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
FAU - Osada, Motonobu
AU  - Osada M
AD  - Merck Biopharma Co., Ltd., An Affiliate of Merck KGaA, Tokyo, Japan.
FAU - Venkatakrishnan, Karthik
AU  - Venkatakrishnan K
AD  - EMD Serono Research and Development Institute, Inc., An Affiliate of Merck KGaA, 
      45 Middlesex Turnpike, Billerica, MA, 01821, USA.
FAU - Khandelwal, Akash
AU  - Khandelwal A
AD  - Merck Healthcare KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany. 
      akash.khandelwal@merckgroup.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT02517398
SI  - ClinicalTrials.gov/NCT02699515
SI  - ClinicalTrials.gov/NCT03840915
SI  - ClinicalTrials.gov/NCT04246489
SI  - ClinicalTrials.gov/NCT02517398
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220906
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (B7-H1 Antigen)
RN  - 0 (Immunologic Factors)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - B7-H1 Antigen
MH  - Clinical Studies as Topic
MH  - *Hemorrhage/chemically induced/prevention & control
MH  - Humans
MH  - *Immunologic Factors/toxicity
MH  - *Neoplasms/drug therapy
MH  - Risk Management
MH  - Transforming Growth Factor beta
PMC - PMC9474582
OTO - NOTNLM
OT  - Clinical pharmacokinetics
OT  - Exposure-response relationship
OT  - Immune checkpoint inhibitor
OT  - Phase 1, 2, 3 trials
OT  - Solid tumors
COIS- Y. Vugmeyster and K. Venkatakrishnan report employment and own stocks at EMD 
      Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate 
      of Merck KGaA. A.-M. Grisic, A.H. Loos, R. Hallwachs, and A. Khandelwal report 
      employment, royalties, and own stocks at Merck. J.J. Wilkins declares no 
      potential conflicts of interest. M. Osada reports employment with Merck Biopharma 
      Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA.
EDAT- 2022/09/07 06:00
MHDA- 2022/09/17 06:00
PMCR- 2022/09/06
CRDT- 2022/09/06 11:14
PHST- 2022/04/05 00:00 [received]
PHST- 2022/08/17 00:00 [accepted]
PHST- 2022/09/07 06:00 [pubmed]
PHST- 2022/09/17 06:00 [medline]
PHST- 2022/09/06 11:14 [entrez]
PHST- 2022/09/06 00:00 [pmc-release]
AID - 10.1007/s00280-022-04468-6 [pii]
AID - 4468 [pii]
AID - 10.1007/s00280-022-04468-6 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2022 Oct;90(4):369-379. doi: 
      10.1007/s00280-022-04468-6. Epub 2022 Sep 6.