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Schedule 1.121: Existing Targets |
• BCMA means B-cell Maturation Antigen. Entrez Gene ID:608. HGNC ID: HGNC:11913 |
• PSMA means Prostate Specific Membrane Antigen. Entrez Gene ID:2346. HGNC ID: HGNC:3788 |
• Her 2 means Human epidermal growth factor receptor 2. Entrez Gene ID:2064. HGNC ID: HGNC:3430 |
• CD20 means Cluster of Differentiation 20. Entrez Gene ID: 931. HGNC ID: HGNC:7315 |
• CD22 means Cluster of Differentiation 22. Entrez Gene ID: 933. HGNC ID: HGNC: 1643 |
• CD123 means Cluster of Differentiation 123. Entrez Gene ID: 3563. HGNC ID: HGNC: 6012 |
• CLL1 means C-type lectin-like molecule. Entrez Gene ID: 160364. HGNC ID: HGNC: 31713 |
• CD3 means Cluster of Differentiation 3. Entrez Gene ID: 917. HGNC ID: HGNC: 1675 |
Schedule 1.129: Failed Target Criteria |
A Research Target shall be deemed a Failed Target if it satisfies at least one of the following conditions: |
1. Those Research Target Products generated and tested with respect to the Research Target campaign does not exhibit an appropriate in vitro selectivity index, defined as at least 10-fold difference in the potency of the Research Target Product on tumor cells expressing the Research Target vs. tumor cells lacking expre... |
2. Those Research Target Products that were advanced into in vivo studies with respect to the Research Target failed to show statistically significant efficacy as judged by comparison to the infusion of sCAR-T cells alone; or |
3. Failure of a Research Target Products with respect to the relevant Research Target to advance past a Decision Point, where the TD-JRC believes in good faith that no Research Target Product could be generated that would advance past such Decision Point given the then-current state of the art. |
Schedule 1.139: FTE Rates |
• For Calibr FTEs, as of the Original Execution Date: $315,000 |
• For AbbVie FTEs, as of the Original Execution Date: $375,000 |
Schedule 1.149: In-License Schedule |
License Agreement between The Scripps Research Institute and California Institute for Biomedical Research dated 1, 2015, as amended. |
Schedule 1.225: PRLR Switch Plan |
[See attached.] |
PRLR Switch Plan |
Plan Rationale and Goals High-level summary of key functional activities for PRLR Switch Plan (ABBV-461+CLBR001) sCAR-T cell therapy for first in human clinical study (Ph1). |
CMC Item # CMC Deliverable, Responsible Party and Notes Activities Timeline (approximate, subject to actual development timelines) |
1 CMC Working Group Calibr and AbbVie A CMC Working Group will be formed by the TD-JRC to discuss project updates, deliverables, and future plans. The CMC working group will meet at least once per Calendar Quarter. Discussion, agreements, and next steps will be documented through meeting minutes. - Any disputes will be... |
2 Contract CLBR001 CMC for clinical readiness SOW#4 (Stage #3-4 Minaris) Calibr will negotiate and finalize with Minaris the contract for Stage 3-4 (Process implementation (Stage 3) and Aseptic Process Simulation and Production Readiness (Stage 4)). Calibr will provide AbbVie with fully executed SOW#4 October 2023 |
3 CLBR001 CMC manufacturing process lock Calibr and Minaris will work together to implement and lock the CLBR001 cell manufacturing protocol prior to initiation of engineering runs in Q1 2024 December 2023 |
4 CLBR001 CMC for clinical readiness SOW#4 (Stage #3-4 Minaris) deliverables Calibr will provide AbbVie documentation supporting Stage 3-4 for CLBR001 CMC including: • Manufacture and testing of non-GMP batches including MBRs, WI / FORMs, and reports • List of NOEs and Deviations for each engineering lot • A Certificat... |
5 Clinical readiness Open GMP suite for clinical manufacturing Calibr and Minaris will complete work to initiate clinical manufacturing (Stage 4 completion) May 2024 |
6 CLBR001 cell product to support nonclinical development (pIND studies) Calibr will be responsible for supplying CLBR001 cell product needed for nonclinical studies to support IND Sept 2023 through IND filing estimated to be May 2024 |
7 ABBV-461 switch to support nonclinical development (pIND studies) Abbvie will be responsible for supplying ABBV-461 switch ENG/tox and DS, DP needed for non-clinical studies to support IND Sept 2023 through IND filing estimated to be May 2024 |
8 Contract CLBR001 CMC for clinical manufacturing (Stage #5 Minaris) Calibr will negotiate and finalize with Minaris the contract for Stage 5 (Clinical Manufacturing). Calibr will provide AbbVie with fully executed SOW#5 March 2024 |
9 CLBR001 CMC Clinical Manufacturing (Stage #5 Minaris) deliverables Calibr will provide AbbVie documentation supporting Stage 5 for CLBR001 CMC including: • Current revisions of all specific GMP documents (MBRs/WI/FORMS/Protocols/Reports) • Executed Batch records for all unit operation steps. • A Certification of Test... |
10 Clinical supplies (CLBR001 cell product) for Ph1 • Calibr will be responsible for the production and delivery to clinical sites of the cell component (CLBR001) of ABBV-461 program for Ph 1 studies (US) • CLBR001 Clinical supplies will be produced under cGMP conditions at Minaris. • Calibr will be responsible for con... |
11 Clinical Supplies (ABBV-461 switch) for Ph1 • Calibr will contract a CRO (ie Sharp) for storage and distribution of ABBV-461. • AbbVie will be responsible for providing drug product with appropriate formulation, vialing, and labeling to storage and distribution CRO selected by Calibr. CRO will be contracted Q1-Q2 20... |
12 ABBV-461 switch stability studies • AbbVie will be responsible for maintaining stability studies of ABBV-461 switch. • AbbVie will provide reports to Calibr as needed to support clinical study. Duration of the Ph1 clinical study |
13 Lentiviral vector (LV1-ENH655-ABBV) • AbbVie will generate and maintain stability studies for the GMP lentiviral vector LV-ENH655-ABBV) used in the CLBR001 CMC process. • AbbVie will provide Calibr with stability reports on LV1-ENH655-ABBV as needed. • AbbVie will be responsible for providing Minaris with LV1-ENH655... |
14 CLBR001 CMC Project Close-out (Stage #6 Minaris) Calibr and Minaris will be responsible for close-out of the CLBR001 CMC after last patient is enrolled and to provide AbbVie: • Calibr will supply to AbbVie the close out report generated by Minaris September 2027, subject to actual clinical trial performance |
15 CMC Regulatory support Calibr will act as the sponsor for IND • Calibr will generate, review, and provide data and reports as needed to support IND. • Calibr will provide Abbvie with data, reports, IND drafts, and final IND as needed • Calibr and AbbVie will jointly participate in responses to Agency on IND question... |
Clinical Item # Clinical Deliverable Activities Timeline |
1 Clinical Phase 1 protocol for CLBR001+ABBV-461 • Calibr will complete the Ph1 clinical protocol for CLBR001+ABBV-461 dose escalation in breast cancer patients for to IND submission • Calibr will provide Abbvie the draft protocol for input, as well as with the final clinical protocol and any amendments. Q2 2024 |
2 KoL and PI interactions Calibr and AbbVie will jointly determine a list of KOLs and potential institutions and investigators who may be approached for feedback and/or participation in the Phase 1 clinical program Q4 2023 |
3 Clinical CRO(s) • Calibr will identify, contract, and manage the clinical CRO(s) and vendors for the Ph1 clinical program (main study + LTFU) • Calibr will provide AbbVie with fully executed contract(s) Q1 2024 |
4 Clinical site identification • Calibr will identify and evaluate clinical sites to participate in the Ph1 clinical program and negotiate/execute contracts with sites via CRO • Calibr will provide AbbVie with final list of sites • Calibr targets first site open to enrollment for the Ph 1 clinical study in Q2/Q3 2024 Q... |
5 Clinical site training • Calibr and clinical CRO will provide clinical sites with protocol-specific training, including sample processing training, that may be required. • Calibr will provide clinical sites with supplies necessary to complete protocol-specific procedures (for example, equipment that may be needed to ... |
6 Phase 1 Clinical trial CBR001+ABBV-461 Dose Escalation in US Calibr will initiate a US-based Phase 1 clinical trial evaluating CLBR001+ABBV-461 dose escalation in breast cancer patients, briefly summarized below: • US-based, phase 1, dose escalation trial to assess the safety and tolerability of the combination of CL... |
7 Long-Term Follow-Up Trial Calibr will establish and serve as Sponsor for a Long-Term Follow-Up clinical trial • Per FDA guidelines, subjects treated with CLBR001+ABBV-461 will be enrolled on the LTFU trial for collection of data on delayed adverse events, including RCL • Additional assessments may also be included af... |
Biomarker and Bioanalytical methods Item # Biomarker Deliverable Activities Timeline |
1 Biomarker Assay Development/Validation (pharmacodynamic markers) Calibr will identify and contract CRO for the specific biomarker assay development and validation • Calibr will Provide development and validation report(s) for the following assays • Flow Cytometry Assays including CAR-T panel and TBNK • 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 • Calibr will Provide development and validation report(s) for the following assays • 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: • Biotin-labelled anti-idiotypic antibody against ABBV-461 • Sulfo-tagged anti-PNE reagent • 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) • 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: • All available clinical data in the EDC up to 3 months post last patient enrollment • Biomarker data, summary and individual analysis report for all patients - - BA method (PK assay) validation reports • Reports for non-clinical studies (IND-enabling studies) • 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 ≥ 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 • 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... |
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