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1 Biomarker Assay Development/Validation (pharmacodynamic markers) Calibr will identify and contract CRO for the specific biomarker assay development and validation β’ Calibr will Provide development and validation report(s) for the following assays β’ Flow Cytometry Assays including CAR-T panel and TBNK β’ Cytokine panel... |
2 Bioanalytical Assay Development/Validation (CLBR001 and ABBV461 PK and ADA) Calibr will identify and contract CRO for the specific bioanalytical assay development and validation β’ Calibr will Provide development and validation report(s) for the following assays β’ CAR-T PK assays by ddPCR in peripheral blood and in so... |
3 Reagents for Bioanalytical method development and assay execution AbbVie to provide Calibr or contracted CRO all reagents necessary for ABBV-461 bioanalytical development including but not limited to: β’ Biotin-labelled anti-idiotypic antibody against ABBV-461 β’ Sulfo-tagged anti-PNE reagent β’ ABBV-461 DS/DP to use as... |
4 Central Lab & Bioanalytical Calibr will identify, contract, and manage central lab(s) for management of samples related to biomarker, bioanalytical, and exploratory assessments for Ph1 clinical study and long-term follow up as necessary June 2024 |
5 Biomarker driven patient selection for clinical trials (if needed) β’ Calibr and AbbVie will explore feasibility and align on the development of a biomarker strategy for patient stratification based on PRLR expression in tumors. It will be determined via the TD-JRC if and how a biomarker strategy would be part of incl... |
Regulatory Item # Regulatory Deliverable Activities Timeline |
1 Calibr will submit pre-IND for ABBV-461+CLBR001 Calibr will author, review, finalize pre-IND documents and submit to support clinical development program, Calibr will provide to AbbVie drafts for input and final version. October 2023-April 2024 |
2 Calibr will submit IND for ABBV-461+CLBR001 Calibr will author, review, finalize IND documents and submit in IND eCTD format to support clinical development program/studies via regulatory agent (contracted through CRO). Calibr will provide to AbbVie drafts for input and final version. June 2024 |
3 Regulatory inquires Calibr will review and address any inquiries from the FDA regarding ABBV-461 program. Calibr seek AbbVie input on responses for input and final version where feasible. Duration of clinical program |
4 Development Safety Update Report (DSUR) Calibr will compile all the information required to file DSUR annually within regulatory deadline; Calibr will provide to AbbVie DSUR. Duration of clinical program |
Appendix A: Final Data Package will include: β’ All available clinical data in the EDC up to 3 months post last patient enrollment β’ Biomarker data, summary and individual analysis report for all patients - - BA method (PK assay) validation reports β’ Reports for non-clinical studies (IND-enabling studies) β’ Final Clinic... |
Appendix B: High-Level Clinical Development Plan and Estimated budget Budget Estimate for 20 patients (1 of 2) |
Appendix B: High-Level Clinical Development Plan and Estimated budget Budget Estimate for 20 patients (2 of 2) |
Appendix B: High-Level Clinical Development Plan and Estimated budget Budget Estimate for 24 patients (1 of 2) |
Appendix B: High-Level Clinical Development Plan and Estimated budget Budget Estimate for 24 patients (2 of 2) |
Clinical Protocol Synopsis A PHASE 1, OPEN-LABEL, DOSE-ESCALATION STUDY EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF THE COMBINATION OF CLBR001, AN ENGINEERED AUTOLOGOUS T CELL PRODUCT, AND ABBV-461, AN ANTIBODY-BASED BIOLOGIC, IN SUBJECTS WITH RELAPSED/REFRACTORY BREAST CANCER (workin... |
Investigational Product CLBR001 + ABBV-461 US FDA Investigational New Drug (IND) Number tbd Protocol Number CBR-xxxx-300x (tbd) Development Phase Phase I Sponsor Name and Address Calibr, a Division of Scripps Research 11119 N Torrey Pines Rd, Suite 200 La Jolla, CA 92037, USA 858-242-1000 Contract Research Organization... |
PROTOCOL SUMMARY Synopsis Short Title: A Phase 1 study of CLBR001 and ABBV-461 in Subjects with locally advanced or metastatic Breast Cancer. Rationale In this protocol, a novel switchable CAR-T cell therapy comprising an autologous CAR-T product (CLBR001, the switchable CAR-T cell [sCAR-T]) and an anti-PRLR Fab (ABBV-... |
phase 2 dose (RP2D). The actual number will depend on the safety and tolerability of the combination of CLBR001 and ABBV-461. |
Subjects will undergo leukapheresis following the screening period and enrollment. Apheresis product will be shipped to a centralized manufacturing facility for production of CLBR001 drug product (contract development and manufacturing organization [CDMO] expected to be contracted and managed by Calibr). Prior to admin... |
Cohorts and escalation CLBR001 (140e6 CAR+ cells per dose) will be administrated to all cohorts and is not planned to be escalated. ABBV-461 will be dose escalated according to BOIN rules. An accelerated dose-escalation design may be used if starting dose is expected to be significantly below predicted efficacious dose... |
Dose Levels and Justification CLBR001 will be dosed at 140e6 CAR+ cells per dose based on prior clinical experience with the same platform. The approach for determining the maximum recommended starting dose (MRSD) of ABBV-461 is expected to be based on the minimum anticipated biological effect level (MABEL) of the in v... |
ABBV-461 is expected to be administered by an intravenous (IV) injection, starting on Day 1 of each cycle. The number of ABBV-461 doses will be based on observed activity of CLBR001 + ABBV-461 in the in vivo efficacy models and the measurement of ABBV-461 PK in mouse, and non-human primate (e.g. once daily D1 through D... |
Lymphodepletion Lymphodepletion is expected to be fludarabine/cyclophosphamide (flu/cy), consistent with CBR-sCAR19-3001 protocol. |
Treatment of CRS / ICANS Treatment of CRS / ICANS will follow ASTCT (Lee et al. 2019) guidelines. |
Treatment Duration Each cycle is expected to be 28 days. Subjects are expected to receive cycles of ABBV-461 switch within the first year after CLBR001 administration. |
Study Duration The study is expected to take 2.5 years to fully enroll. The total duration of the study is expected to be 3.5 years. The actual number will depend on outcomes, safety, and tolerability of the combination of CLBR001 and ABBV-461, and the duration that subjects remain on treatment. |
Long-Term Follow Up All subjects who receive CLBR001 will roll over to a long-term follow up (LTFU) monitoring study after completion, or early termination, of the primary 12-month treatment protocol. The LTFU will last 14 years for a total observation period of 15 years. |
Number of Investigators and Study Centers Approximately 6-10 Investigators and study centers in the United States (US) are expected to participate in this study. The final number will be determined based on feasibility assessment in clinical start-up. |
Inclusion Criteria The study is expected to enroll third-line or later breast cancer patients. Patients will have measurable disease in accordance with RECIST criteria. Prolactin receptor (PRLR) positivity is not expected to be used as an inclusion criterion for dose escalation. A full list of inclusion criteria will b... |
Key inclusion criteria are expected to include ability to understand and sign informed consent, at least two lines of adequate prior therapy (not including prior radiation or surgery), adequate time between prior treatments and leukapheresis, men or women age β₯ 18, Eastern Oncology Group performance status (ECOG PS) 0 ... |
Exclusion Criteria A full list of exclusion criteria will be included in the final protocol following discussions between Calibr and AbbVie teams. |
Key exclusion criteria will include, pregnant or lactating women, clinically significant infection within 4 weeks prior to CLBR001 dose, active infection, allogeneic stem cell transplantation (SCT) at any time, and active central nervous system (CNS) disease. |
Efficacy Evaluations Efficacy will be measured by RECIST version 1.1. |
Safety Evaluations Safety assessments include observation of adverse events (AE), serious AEs (SAEs), laboratory evaluations, vital signs, electrocardiograms (ECGs), full and abbreviated physical examinations, ECOG PS, ADA and neutralizing ADA, and DLTs. The safety of CLBR001+ABBV-461 will be evaluated based on review ... |
CRS / ICANS Treatment of CRS / ICANS will follow ASTCT (Lee et al. 2019) guidelines. |
DLT Definitions A DLT is a study drug-related AE occurring within the DLT window based on NCI CTCAE version 5.0 or ASTCT (Lee et al. 2019) for CRS or ICANS, where appropriate. The DLT window is expected to be 28 days post cycle 1, day 1 (C1D1) (first dose of ABBV-461). |
Pharmacokinetics CLBR001: Blood samples will be collected to quantify CLBR001. ABBV-461: Blood samples will be collected to quantify ABBV-461 concentration. Samples will be tested by a designated contract laboratory. |
Pharmacodynamics & Biomarkers PD markers may include cytokines (central and/or local lab processing as appropriate) and immunophenotyping of CLBR001 cells from peripheral blood. Samples will be tested by a designated contract laboratory. Archival tumor tissue will be evaluated for PRLR expression and other biomarkers a... |
Immunogenicity Antibodies to CLBR001 and ABBV-461 (ADA) will be evaluated in serum or plasma samples collected from all subjects. The detection and characterization of antibodies to CLBR001 and ABBV-461 will be tested by a designated contract laboratory where appropriate |
Data Package (AbbVie) Data package will be defined as top-line data 3 months post-last subject first dose. |
References Lee, D. W., B. D. Santomasso, F. L. Locke, A. Ghobadi, C. J. Turtle, J. N. Brudno, M. V. Maus, J. H. Park, E. Mead, S. Pavletic, W. Y. Go, L. Eldjerou, R. A. Gardner, N. Frey, K. J. Curran, K. Peggs, M. Pasquini, J. F. DiPersio, M. R. M. van den Brink, K. V. Komanduri, S. A. Grupp, and S. S. Neelapu. 2019. '... |
Schedule 1.273: Target Research Plan |
[See attached.] |
Schedule 1.273: Target Research Plan β’ The budget outlined in this schedule will be used in reference to all sections in the Agreement that reference the budget in the Target Research Plan. AbbVie will reimburse Calibr for up to 18 FTEs at the FTE Rate per Calendar Year/during the period of the Research Term, or an agg... |
1. Fab Switch sCAR-T Workflow (Gantt "Proposed Discovery Fab Switch sCAR-T Workplan") |
Component Activities Requirements Deliverables Responsible Timeframe TD-JRC |
Hybridization campaign in humanized transgenic mice Chevron A Target plasmid, protein of target and target positive transduced cells (and isogenic control cell line) Sequence and alignment of groups of different binder families/epitope bins AbbVie to conduct for proprietary targets 9 months |
Switch: Target Antibody Sequences Chevron B Up to 9 mAb variable region sequences per tumor target Evidence of target binding by delivered families/epitope bins AbbVie to deliver sequences, epitope binning, and cellular binding affinity to Calibr 3 months |
Switch: Library of design of mAb candidates Chevron 1 6 switch grafting designs (each peptide grafting location is considered a design candidate) + base switch Fab control per mAb variable sequence (7 proteins per mAb variable region sequence) Calibr to deliver sequences of switches to AbbVie Calibr to develop 6 switch... |
Switch: Protein production of candidates Chevron 2 Expression of 6 switch grafting designs (each peptide grafting location is considered a design candidate) + base Fab control per mAb variable sequences (7 proteins per mAb variable region sequence). Calibr to express sufficient quantity of switches for in vitro activit... |
sCAR-T + Switch: In vitro activity screen Chevron 3 In vitro evaluation to test the functional activity of each switch in the presence of antigen-positive and antigen-negative target cells. Activity in the presence of antigen negative cells to investigate the potential of candidates to cause off-target or antigen-indep... |
sCAR-T + Switch: In vitro activity profiling (dose-dependence) Chevron 4 In vitro activity on selected candidates to be demonstrated dose dependent on antigen-positive cells. Selectivity index (SI) between antigen positive and antigen-negative tumor cell line to be determined. Calibr to deliver data package which inclu... |
Switch: Protein characterization/ profiling (R&D) Chevron 5 Biophysical characterization of 9 selected candidates to occur simultaneously with sCAR-T + Switch in vitro activity profiling Biophysical characterization of 9 selected candidates to occur simultaneously with sCAR-T + Switch in vitro activity profiling. AbbVi... |
sCAR-T + Switch: In vitro activity profiling (healthy tissue/cell line panel) Chevron 6A In vitro activity on 3 prioritized candidate switches to be demonstrated in dose dependent format on healthy tissue derived cells. Selectivity index (SI) between antigen positive and healthy tissue derived cells line to be determin... |
In vivo efficacy assessment in NSG mice (single switch) Chevron 6B Assess in vivo activity of sCAR-T + prioritized 3 Switches individually in appropritate xenograft tumor model setting including nontransduced T cells and sCAR-T with irrelevant control switch (SWI019). Demonstrate reduction of tumor burden in NSG (immun... |
In vivo efficacy assessment in NSG mice (dual switch). Chevron 7 Assess in vivo activity of sCAR-T + two candidate Fab switches targeting different antigens in a single in vivo xenograft model model. Model parameters, benchmaks, and controls to be similar to above. Analyses to follow parameters outlined above. AbbVie t... |
Lead Fab switch selection and manufacture and in vitro validation of materials for additional studies Chevron 8 Selection of one prioritized candidate Fab switch sequence for each tumor antigen targets (2 Fab switches total). Sufficient candidate and control Fab switch protein expression and purification sCAR-T transdu... |
In vivo efficacy in Xeno model in NSG mice to support IND (Definitive mouse model aka GLP/ GLP-like model) Chevron 9 Assess in vivo activity of sCAR-T with Fab switches in appropriate preclinical efficacy model to support IND package Efficacy analysis of sCAR-T to support IND pacakage Calibr to design and conduct effic... |
Confirmatory in vivo efficacy assessment in PDX tumor model in NOD Scid Mice Chevron C Assess in vivo activity of lead sCAR-T + Switch in appropritate PDx tumor model setting including untransduced T cells and sCAR-T with irrelevant control switch (SWI019). Demonstrate reduction of tumor burden in NOD Scid (immunodefic... |
Transgene knockdown sCAR-T (shRNA knockdown sCAR-T) Component Activities Requirements Deliverables Responsible Timeframe TD-JRC |
Base Materials Chevron 10 sCAR-T and Herceptin Fab switch will be used as a platform base for work flow activities Calibr 1 month |
Production and testing of optimizing shRNAs for transgene removal Chevron 10 shRNA sequence confirmation of transgene removal/knockdown on T cells (5 shRNA per target) of up to 3 target genes Calibr/AbbVie to identify 3 genes for knockdown with putative impact on activity, memory, persistence, or resistance to immunosu... |
shRNA-sCAR-T sub-cloning Chevron 10 Sub cloning of the candidate shRNA sequences to Calibr's previously constructed sCAR-T vector, harboring the mu6 shRNA promoter and cloning site Calibr to provide sequence confirmation of each of the 15 candidates and controls (Luc-based shRNAs β already made at Calibr). Calibr 2 mon... |
Transduction of armoured sCAR-T Chevron 11 Demonstration of T cell transfection and expression of sCAR-T and shRNA Data confirmation of sCAR-T expression, shRNA expression. Calibr to provide data and results confirming sCAR-T and shRNA expression. 4 months |
In vitro phenotypic and functional characterization Chevron 12 Confirmation of sCAR-T expression and transgene knockdown on transduced T cells and in vitro functional analysis Confirmation of T cell transduction and T cell phenotype analysis In vitro assay activity data to be generated using Target Antigen (Ag) +/- cel... |
In vivo efficacy assessment in NSG mice Chevron 13 Assess in vivo activity of standard sCAR-T compared to transgene knockdown sCAR-T in appropriate preclinical efficacy model Efficacy analysis of standard sCAR-T compared to armoured sCAR-T Calibr and AbbVie to design efficacy studies. Calibr to deliver results and data... |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 14 Repeat in vitro development in mouse background on a single target candidate with up to 5 shRNA β necessary to measure benefit of DNR construct in competent immune system Repeat in vitro development, can overlap with human system Calibr op... |
In vivo efficacy assessment in surrogate mice Chevron 15 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate syngeneic model Efficacy AbbVie to deliver data and results to Calibr 6 months (depending upon models chosen) |
Dominant Negative Receptor (DNR) sCAR-T Selection of DNRs Chevron 16 Up to 3 DNRs to be tested. Calibr/AbbVie to identify candidate TME sequences and background data/rationale and any confirmatory or preliminary studies on 3 DNRs to be tested in the Calibr sCAR-T platform. Include FTO analysis (this may be waived with ... |
DNR sCAR-T sub-cloning Chevron 16 Subcloning of the 3 DNR genes into a bicistronic lentiviral transfer vector harboring the sCAR-T. Calibr to provide AbbVie with sequence confirmation of 3 DNR genes in up to 2 formats (T2A and IRES) with the sCAR-T lentiviral transfer vector β up to 6 constructs Calibr 3 months |
Transduction of armoured sCAR-T Chevron 17 Demonstration of T cell transfection and expression of sCAR-T and dominant negative receptor Data confirmation of sCAR-T expression, dominant negative receptor expression Calibr to provide data and results confirming sCAR-T and dominant negative receptor expression 2 months |
Phenotypic and functional characterization Chevron 18 Confirmation of sCAR-T expression and dominant negative receptor expression on transduced T cells and in vitro functional assessment Confirmation of T cell transduction T cell phenotype analysis. In vitro assay activity data to be generated using Target Antigen (Ag)... |
In vivo efficacy assessment in NSG mice Chevron 19 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to AbbVie. 8 months (depending upon models chosen) |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 20 Repeat in vitro development in mouse background with a single DNA candidate β necessary to measure benefit of DNR construct in competent immune system Repeat in vitro development, can overlap with human system Calibr to design murine react... |
In vivo efficacy assessment in syngeneic model mice Chevron 21 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model. Efficacy Calibr to deliver data and results to AbbVie. 6 months (depending upon models chosen) |
Tumor Microenvironment Armoured sCAR-Ts Selection of TME armoured transgenes Chevron 22 Up to 3 TME transgenes to be tested β inducible vs non-inducible (NFAT) promoters to be discussed based on nature of target TME transgenes. Joint Research Committee may choose to nominate all armoured options in this category and as... |
Subcloning & expression of transgene Chevron 22 Subcloning of the chosen TME transgenes into a bicistronic lentiviral transfer vector harboring the sCAR-T. Calibr to provide AbbVie with sequence confirmation of TME transgenes in up to 2 formats (inducible vs non-inducible) with the sCAR-T lentiviral transfer vector Cal... |
Transduction of peripheral blood production of armoured sCAR-T Chevron 23 Demonstration of T cell transfection and expression of sCAR-T and tumor microenvironment transgene Data confirmation of sCAR-T expression, tumor microenvironment transgene expression Calibr to provide data and results confirming sCAR-T and transg... |
Phenotypic and functional characterization Chevron 24 Confirmation of sCAR-T expression and transgene expression on transduced T cells and in vitro functional assessment Confirmation of T cell transduction (sCAR-T expression and transgene expression) T cell phenotype analysis In vitro assay activity data to be generate... |
In vivo efficacy assessment in NSG mice Chevron 25 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to AbbVie 8 months (depending upon models chosen) |
In vitro efficacy and surrogate safety biomarker in syngeneic animals Chevron 26 Repeat in vitro develoment in mouse background β necessary to measure benefit of transgene construct Repeat in vitro development, can overlap with human system Cablir to design murine reactive switch or to obtain human Her2 transgeneic mou... |
In vivo efficacy assessment in syngeneic mice Chevron 27 Assess in vivo activity of armoured sCAR-T versus non-armoured sCAR-T in appropriate efficacy model Efficacy Calibr to deliver data and results to Abbvie 6 months (depending upon models chosen) |
2. sTCR Switch sCAR-T Workflow (Gantt β "Proposed Discovery sTCR Switch sCAR-T Workplan") a. Standard Platform |
Component Activities Requirements Data Deliverables Comments Timeframe TD-JRC |
Transfer of soluble TCR Sequences Chevron A One control soluble TCR sequence and 3-6 candidate soluble TCR sequences with a range of binding affinities AbbVie: TCR sequences and evidence of target binding and affinities AbbVie to deliver Control TCR sequence and one candidate TCR sequence with MHC binding data to be de... |
Design of sTCR switch format library with control and first candidate TCRs Chevron 1 Switch grafting designs to be established for soluble TCR-based switches (each format, domain orientation, and peptide grafting location is considered a design candidate) using a control and the first candidate TCR Calibr to design can... |
Production of sTCR switch proteins based on control and first candidate TCRs Chevron 2 sTCR switch grafting designs (each format and peptide grafting location is considered a design candidate) based on control and first candidate TCR to be tested for expression Calibr to express sufficient quantity for in vitro activit... |
sCAR-T + sTCR Switch: In vitro activity screen of sTCR switches based on control and first candidate TCR Chevron 3 In vitro evaluation to test the functional activity of each candidate TCR switch protein in the presence of T2 target cells loaded with cognate peptide an irrelevant peptide. 3 independent human T cell don... |
Design of sTCR switch format library with additional candidate TCRs Chevron 4 Up to 3 switch grafting designs (each format, domain orientation and peptide grafting location is considered a design candidate), where selected designs are guided by control TCR expression and activity results) per TCR sequence Calibr to des... |
Production of sTCR switch proteins based on additional candidate TCRs Chevron 5 sTCR switch grafting designs (each format and peptide grafting location is considered a design candidate) based on additional candidate TCRs to be tested for expression Calibr to express sufficient quantity for in vitro activity screen (bel... |
sCAR-T + sTCR Switch: In vitro activity screen of sTCR switch proteins based on additional candidate TCRs Chevron 6 In vitro evaluation to test the functional activity of each switch in the presence of antigen-positive vs. antigen-negative target cells. 3 independent human T cell donors/construct will be used to genera... |
sCAR-T + sTCR Switch: In vitro activity profiling with healthy tissue/cell line panel Chevron 7 In vitro activity on 3 prioritized candidate switches to be demonstrated in dose dependent format on HLA allele-matched healthy tissue derived cells. Selectivity index (SI) between antigen positive and healthy tissue derived... |
In vivo sCAR-T + sTCR switch efficacy assessment in NSG mice Chevron 8 Assess in vivo activity of sCAR-T + prioritized 3 candidate sTCR switches in appropritate Xeno tumor model setting including nontransduced T cells and sCAR-T with control sTCR switch. Demonstrate reduction of tumor burden in NSG (immunodeficient) mi... |
Lead sTCR switch selection, manufacture and in vitro validation of materials for hand off to AbbVie for PDX model in Chevron 9 Selection of one prioritized candidate sTCR switch sequence. Sufficient candidate and control sTCR switch protein expression and purification sCAR-T transduction vector, and transduced, frozen ... |
In vivo efficacy in Xeno model in NSG mice to support IND (Definitive mouse model aka GLP/ GLP-like model) Chevron 13 Assess in vivo activity of sCAR-T and sTCR switch in appropriate preclinical efficacy model to support IND package Efficacy analysis of sCAR-T to support IND pacakage Calibr to design efficacy studies i... |
Confirmatory In vivo efficacy assessment in PDX/Xeno tumor model in NOD Scid Mice Chevron B Assess in vivo activity of sCAR-T cells + lead sTCR swtich in appropritate PDx/Xeno tumor model setting including untransduced T cells and sCAR-T with irrelevant control switch. Demonstrate reduction of tumor burden in NOD Scid ... |
Component Activities Requirements Deliverables Responsible Timeframe FTE |
Armoured sTCR Switch sCAR-T Chevron 10 Work plan will utilze platform base determined from armoured Fab Switch sCAR-T work plan Calibr 1 month |
Lead selection, manufacture, and in vitro validation to support armoured sTCR Switch sCAR-T in vivo work Chevron 11 Confirmation of Armoured sCAR-T expression on transduced T cells, prioritized sTCR switch sequence, and in vitro functional analysis. Confirmation of transgene expression. Calibr to generate in vitro assa... |
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