Clinical Investigation of a Humanized Anti-CD47 Antibody in Targeting Cancer Stem Cells in Acute Myelodi Leukaemia (and Solid Tumours).

Lead Research Organisation: University of Oxford
Department Name: Weatherall Inst of Molecular Medicine

Abstract

Most normal tissues are maintained by a small number of stem cells that can both self-renew to maintain stem cell numbers, and also give rise to progenitors that make mature cells. We have shown that normal stem cells can accumulate mutations that cause progenitors to self-renew out of control, forming cancer stem cells (CSC). CSC make tumors composed of cancer cells, which are more sensitive to cancer drugs and radiation than the CSC. As a result, some CSC survive therapy, and grow and spread.

We sought to find therapies that include all CSC as targets. We found that all cancers and their CSC protect themselves by expressing a 'don't eat me' signal, called CD47, that prevents the innate immune system macrophages from eating and killing them. We have developed a novel therapy (anti-CD47 blocking antibody) that enables macrophages to eliminate both the CSC and the tumors they produce. This CIRM Grants System - Administration https://grants.cirm.ca.gov/applicant/grant_app/print/3385 anti-CD47 antibody eliminates human cancer stem cells when patient cancers are grown in mice. At the time of funding of this proposal, we will have fulfilled FDA/MHRA requirements to take this antibody into clinical trials, showing in animal models that the antibody is safe and well-tolerated, and that we can manufacture it to MHRA/FDA specifications for administration to humans.

Here, we propose the initial clinical investigation of the anti-CD47 antibody with parallel first-in-human Phase 1 clinical trials in patients with either Acute Myelogenous Leukemia (AML) or separately a diversity of solid tumors, who are no longer candidates for conventional therapies or for whom there are no further standard therapies. The primary objectives of our Phase I clinical trials are to assess the safety and tolerability of anti-CD47 antibody. The trials are designed to determine the maximum tolerated dose and optimal dosing regimen of anti-CD47 antibody given to up to 42 patients with AML and up to 70 patients with solid tumors. While patients will be clinically evaluated for halting of disease progression, such clinical responses are rare in Phase I trials due to the advanced illness and small numbers of patients, and because it is not known how to optimally administer the antibody. Subsequent progression to Phase II clinical trials will involve administration of an optimal dosing regimen to larger numbers of patients. These Phase II trials will be critical for evaluating the ability of anti-CD47 antibody to either delay disease progression or cause clinical responses, including complete remission. In addition to its use as a stand-alone therapy, anti-CD47 antibody has shown promise in preclinical cancer models in combination with approved anti-cancer therapeutics to dramatically eradicate disease.

Thus, our future clinical plans include testing anti-CD47 antibody in Phase IB/II studies with currently approved cancer therapeutics that produce partial responses. Ultimately, we hope anti-CD47 antibody therapy will provide durable clinical responses in the absence of significant toxicity.

Technical Summary

Many cancers are organized as a cellular hierarchy initiated and maintained by cancer stem cells (CSC). CSC comprise a subset of tumor cells that are relatively resistant to current therapy, which often shrink tumors, but do not lead to long-term cures. Such cures require strategies to target all the CSC. CD47 is a immunomodulatory protein expressed on the surface of CSC and cancer cells from nearly all human tumors. CD47 binds SIRP-alpha on phagocytes, which delivers an inhibitory signal to block phagocytosis. CSC and cancer cells upregulate CD47 expression, presumably to suppress phagocytic attack. This proposal outlines a clinical development plan to evaluate the safety, tolerability, and efficacy of our therapeutic, the humanized anti-CD47 antibody Hu5F9-G4. Hu5F9-G4 is a blocking anti-human CD47 antibody that prevents the binding of CD47 to SIRP-alpha, disrupting its inhibitory signal, and enabling the phagocytic removal of CSC and cancer cells. In xenograft models, we have demonstrated that Hu5F9-G4 has potent efficacy against AML. In non-human primate toxicokinetic studies, Hu5F9-G4 was well-tolerated at doses able to achieve sustained serum levels in a potentially therapeutic range. Simultaneously, we generated a cGMP-qualified master cell bank, and have initiated GLP/GMP manufacturing of Hu5F9-G4. We have had positive initial regulatory interactions with the FDAand MHRA in the UK, and and are on track to file two separate IND/IMPDs, one for AML, and one for solid tumors by early 2014. Here, we propose parallel first-in-human Phase 1 clinical trials in the US and UK of Hu-5F9-G4 in patients with either AML or separately a diversity of solid tumors for whom there are no further standard therapies. The primary objective will be to assess the safety and tolerability of Hu5F9-G4, to identify the maximum tolerated dose (MTD) or optimal biologically effective dose (OBED), and to get a preliminary assessment of tumor reduction for further efficacy studies.

Planned Impact

1. Health care and economic benefits to UK and world wide: There are 2200 new AML cases/year in the UK. 80% of patients are >60 years of age; in an aging population, the disease is becoming more common. Current curative therapy is restricted to medically fit patients, usually <70 years old (~30% of patients). It consists of 2-4 cycles of toxic chemotherapy. A patient spends 3-4 weeks/cycle receiving expensive in-patient care (cost ~£20000/cycle/patient). In ~30% of patients this is followed by an allogeneic blood stem cell transplant (cost £45-60 000/patient). Even this programme only cures 40-50% patients <60 years old. Direct treatment cost to NHS hospitals ~£60-120 000/patient. Annual cost for 660 patients (30% of 2200 who receive curative approach) ~£40M-£80M. This does not include costs: (i) in primary care (ii) loss of earning (iii) tax revenue (iii) care at home (iv) care of problems secondary to initial treatment - e.g. chemotherapy-induced second malignancies (5-10% of patients). ~70% of AML do not receive curative therapy and 98% of these patients die within 4 months. They receive palliative supportive care. Some are entered into Phase I/II/III trials of newer therapies; data so far show none are curative and may benefit 10-40% of patients.

We plan to proceed to 2 Phase II trials (i) elderly untreated AML population (ii) younger patients with minimal residual disease. If Phase II trials show an efficacy signal we will move rapidly to a randomised UK AML Working Party driven Phase II/III looking for an impact on (i) overall survival (currently only 2% in elderly unfit AML patients and 30% in MRD+ve young patients), (ii) improved quality of life, and reduced use of health care resources. We will build in QoL assessment and health care utilisation into the randomised Phase II/III trials.

2. Establishing new class of therapy for AML (and cancers more broadly): If safe, and if the AML and solid trials shows an efficacy signal, it establishes CD47 as a noherapeutic target and targeting programmed cell removal as a novel target pathway. This will impact the whole cancer community.

3. Ability to shape the Anti-CD47 Trial Programme: If Phase I/II programmes are successful it will allow UK investigators to lead, design and deliver pivotal licencing Phase III studies. This will impact on and build (i) knowledge, experience and training of UK teams (ii) a trial programme addressing UK health care needs (iv) world-wide reputation of UK AML clinical and translational programmes (iv) potentially allow to access anti-CD47 therapeutics at reduced cost.

4. Intellectual Property (IP) of clinical and laboratory dataset: The clinical and laboratory dataset from the Phase I/II trials will be important for design, submission and delivery of licencing Phase III studies. This IP will be jointly owned by Universities of Oxford and Stanford. With Stanford we will seek further funding for Phase III trials. The Stanford and Oxford groups want to lead a joint long-term programme for taking anti-CD47 to market.

5. Intellectual Property (IP) of LSC monitoring flow cytometry panel: University of Oxford have IP on aspects of the immunophenotyping panel and joint IP with Becton Dickinson and Stanford on other aspects of the flow cytometry panel. This panel has potential commercial value to identify patients who will respond to (i) anti-CD47 therapy (ii) new therapeutics directed against other stem cell antigens and (iii) identify antibody combination directed against different leukaemic stem cell antigens. Please see letter from Dr Richard Reschen from Issis Innovation.

6. Training of all staff directly involved in the programme and boosting the knowledge economy

7. Provide a paradigm (and thus incentive) for academics take therapeutic targets into clinical practice (particularly through the Phase I study setting) without commercial support thereby increasing value of the therapeutic product.

Publications

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publication icon
Craddock CF (2017) Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature. in Clinical cancer research : an official journal of the American Association for Cancer Research

publication icon
Ivey A (2016) Assessment of Minimal Residual Disease in Standard-Risk AML. in The New England journal of medicine

 
Description Haematology and Stem Cell Theme Oxford Biomedical Research Centre (NIHR)
Amount £5,000,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2017 
End 03/2022
 
Description LLR - Leukaemia & Lymphoma Research. CTAP (Clinical Trial)
Amount £308,470 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2015 
End 02/2018
 
Description Clinical Trial of Anti-CD47 
Organisation Leeds Teaching Hospitals NHS Trust
Department Department of Clinical Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation Royal Liverpool University Hospital
Department Department of Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation Stanford University
Department Stem Cell Institute Stanford
Country United States of America 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation The Christie NHS Foundation Trust
Department Haematology and Transplant Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Hospitals 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University Hospital of Wales
Department Department of Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University of Nottingham
Department Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University of Oxford
Department Department of Oncology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Collaboration on therapy of high risk MDS and AML. 
Organisation University of Birmingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Understanding AML Leukaemic stem cell biology. Assessment of Leukaemic stem cells (LSC) as a marker of minimal residual disease. This is evaluated using samples from clinical trials.
Collaborator Contribution Clinical Trial Lead
Impact Quek L*, Ferguson P*, Metzner M, Ahmed I, Kennedy A, Garnett C, Jeffries S, Walter C, Piechocki K, Timbs A, Danby R, Raghavan M, Peniket A, Griffiths M, Bacon A, Ward J, Wheatley K, Vyas P*, Craddock C*. Mutational Analysis of Disease Relapse in Patients Allografted for Acute Myeloid Leukemia Khan N, Hills RK, Knapper S, Steadman L, Qureshi U, Rector JL, Bradbury C, Russell NH, Vyas P, Burnett AK, Grimwade D, Hole PS, Freeman SD. Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia PLoS One. 2016 Sep 26;11(9):e0163291. PMID: 27669008 Craddock C, Jilani NY, Siddique S, Yap C, Khan JN, Nagra S, Ward J, Ferguson P, Hazlewood P, Buka R, Vyas P, Goodyear OC, Tholouli E, Crawley C, Russell N, Byrne J, Malladi R, Snowden JA, Dennis M. Tolerability and clinical activity of post-transplant Azacitidine in patients allografted for Acute Myeloid Leukaemia treated on the RICAZA trial. Biol Blood Marrow Transplant. Sep 9. pii: S1083-8791(15)00609-6. doi: 10.1016/j.bbmt.2015.09.004. (2015). Bradbury C, Houlton AE, Akiki S, Gregg R, Rindl M, Khan J, Ward J, Khan N, Griffiths M, Nagra S, Hills R, Burnett A, Russell N, Vyas P, Grimwade D, Craddock C, Freeman SD. Prognostic value of monitoring a candidate immunophenotypic leukemic stem/progenitor cell population in patients allografted for acute myeloid leukemia. Leukemia. 29 p988-91. (2014) PMID:25425198. Craddock C, Goardon N, Quek L, Freeman S, Siddique S, Raghavan M, Schuh A, Grimwade D, Virgo P, Hills R, McSkeane T, Arrazi J, Gilkes A, Knapper, Adam Ivey, Brookes C, Miles O, Davies B, Chaudhury S, Pollard T, Price A, Atzberger A, Wall K, Kaur H, Griffiths M, Cavenagh, Majeti R, Weissman I, Burnett A, Vyas P. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukaemia 27:p1028-36 (2013). Goodyear O, Dennis M, Loke J, Jilani N, Siddique S, Ryan G, J Nunnick, Khanum R, Raghavan M, Cook M, Snowden J, Griffiths M, Russell N, Yin J, Crawley C, Cook G, Vyas P, Moss P, Malladi R, Craddock C. Azacitidine Induces Expansion of Regulatory T Cells and Induces a Tumor Antigen Specific Response after Allogeneic Stem Cell Transplantation in patients with AML. Blood. 119: p3361-9. (2012). Co-administration of Vorinostat Does Not Improve Outcome of Patients with of Acute Myeloid Leukemia Treated with Azacitidine Charles Craddock, MD, PhD1, Aimee E Houlton, BSc, MSc2*, Lynn Swun Quek, DPhil, FRCPath, Paul Ferguson, MBChB MRCP PhD3; Emma Gbandi, Corran Roberts (affiliation and degree needed), *, Marlen Metzner, Alison Kennedy, Manoj Raghavan4*, Sandeep Nagra1*, Louise Dudley, BSc, MRes5*, DPhil, MBBS6*, Sharon Love, Jamie D. Cavenagh7, Michael Dennis, FRCPath8*, Mary Frances McMullin, MD9, Srinivas P Pillai10*, Richard Kelly, BSc, MD11*, Shamyla Siddique12*, Keith Wheatley, DPhil13 and Paresh Vyas, BM, DPhil, FRCP, FRCPath14 Submitted Grants: 2015-2018 Therapy Acceleration Programme £92 778. Leukaemia Lymphoma Research Funded Trial Infrastructure Programme
Start Year 2012
 
Description WGS and additional biologic studies of haem tumours. 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Design of the program of WGS and integrated multi-"omic" reseatch program on AML UK NCRI AML clinical trial samples to define clonal structures in human AML and how they change in response to therapy. To determine molecular and cellular mechanisms of therapy resistance.
Collaborator Contribution University of Oxford - Lead of AML GECIP (Vyas) and overall haem GECIP (Schuh) University of Cardiff - Sponsor of Trial
Impact Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, Burnett A, Knapper S. The targeted histone deacetylas inhibitor tefinostst (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget. 2016 Feb 25. doi: 10.18632/oncotarget.7692. PMID: 26934551 Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths, M, Solomon E, McCaughan F, Linch D, Gale R, Vyas P, Freeman S, Russell N, Burnett, A and Grimwade D, for the UK National Cancer Research Institute AML Working Group. Assessment of Minimal Residual Disease in Standard Risk AML. NEJM 374 p422-33. (2016). PMID: 26789727
Start Year 2015
 
Description WGS and additional biologic studies of haem tumours. 
Organisation University of Oxford
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Design of the program of WGS and integrated multi-"omic" reseatch program on AML UK NCRI AML clinical trial samples to define clonal structures in human AML and how they change in response to therapy. To determine molecular and cellular mechanisms of therapy resistance.
Collaborator Contribution University of Oxford - Lead of AML GECIP (Vyas) and overall haem GECIP (Schuh) University of Cardiff - Sponsor of Trial
Impact Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, Burnett A, Knapper S. The targeted histone deacetylas inhibitor tefinostst (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget. 2016 Feb 25. doi: 10.18632/oncotarget.7692. PMID: 26934551 Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths, M, Solomon E, McCaughan F, Linch D, Gale R, Vyas P, Freeman S, Russell N, Burnett, A and Grimwade D, for the UK National Cancer Research Institute AML Working Group. Assessment of Minimal Residual Disease in Standard Risk AML. NEJM 374 p422-33. (2016). PMID: 26789727
Start Year 2015
 
Title AG221 AML-005: 
Description A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral A-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited. 
 
Title Camellia trial 
Description First-in-class Phase I trial of Humanized Monoclonal Antibody anti-CD47 in Acute Myeloid Leukemia. This is an academically funded, 7-year collaboration between my laboratory and Weissman Laboratory Stanford University. Sponsored by Stanford University. Oxford University is Sponsor in the EU. Oxford Oncology Clinical Trials Unit is running this multi-centre UK trial. Trial will complete in 6/2017. Phase II trials planned. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This first-in-class trial of a new monoclonal therapeutic antibody provides a rare example of academically funded work going from a laboratory observation through to development, manufacture and pre-clinical testing of a clinical therapuetic all the way to first clinical trial within the envelope of an entirely academically funded program. This work is a collaboration between my laboratory, my clinical work in Oxford, the Oxford Clinical Oncology Early phase Trial Unit, the UK AML NCRI Clinical Trial Group and Stanford Unviersity. I am CI of the AML trial. The Stanford PI Dr Weissman has established a spin out company CD47 Inc to take this program further in clinical development. 
 
Title Celgene Aza-AML-001: 
Description Phase 3, Multicenter, Randomized, Open-label, Study Of Azacitidine Versus Conventional Care Regimens For The Treatment Of Older Subjects With Newly Diagnosed Acute Myeloid Leukaemia. Vyas was local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Closed
Clinical Trial? Yes
Impact Has led to EMA licence for Aza for AML. NICE refused to fund under TA. Celgene will put forward a patient access scheme for UK patients. 
 
Title Celgene Aza-MDS-001: 
Description A Multicenter, Randomized, Open-Label, Parallel-Group, Phase 3 Trial Of Subcutaneous Azacitidine Plus Best Supportive Care Versus Conventional Care Regimens Plus Best Supportive Care For The Treatment of Myelodysplastic Syndromes (MDS). Vyas is local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Led to licencing of Aza for MDS. NICE approved drug. Now standard of care for this patient group. 
 
Title Celgene MDS003 
Description A Phase 3, Multicenter, Randomized, Double-blind Study To Compare The Efficacy And Safety Of Oral Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care In Subjects With Red Blood Cell Transfusion-dependent Anemia and Thrombocytopenia Due To IPSS Lower-risk Myelodysplastic Syndromes. Vyas is UK national CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This Phase III licencing study will provide clincial dataset that could potential licence oral Azacitidine. 
 
Title Evaulation of anti-PD-L1 in high risk MDS and AML. 
Description A Randomized, Multicenter, Open-label, Phase 2 Study Evaluating The Efficacy And Safety of Azacitidine Subcutaneous In Combination with Durvalumab (MEDIA4736) In Previously Untreated subjects With Higher-risk Myelodysplastic Syndromes (MDS) Or In Elderly (= 65 years) Acute Myeloid Leukemia (AML) Subjects Not Eligible For Hematopoietic Stem Cell Transplantation (HSCT). Vyas is local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited 
 
Title IDH2 inhibitor trial 
Description A PHASE 3, MULTICENTER, OPEN-LABEL, RANDOMIZED STUDY COMPARING THE EFFICACY AND SAFETY OF AG-221 (CC-90007) VERSUS CONVENTIONAL CARE REGIMENS IN OLDER SUBJECTS WITH LATE STAGE ACUTE MYELOID LEUKEMIA HARBORING AN ISOCITRATE DEHYDROGENASE 2 MUTATIO International Phase III trial of a first-in-class oral IDH2 inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene. Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact still awaited. 
 
Title Novartis Telesto Trial 
Description A multi-center, randomized, double-blind, placebo- controlled clinical trial of deferasirox in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload (TELESTO) International Phase III trial of an oral iron chelator in Myelodsplastic Syndrome. Sponsored by Novartis. Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited. Trial data closed and data being analysed. 
 
Title RavVa trial: 
Description Phase II Randomised Trial of 5-Azacitidine versus 5- Azacitidine in combination with Vorinostat in patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes Ineligible for Intensive Chemotherapy). 250 patients. Fully recruited. Vyas is co-Investigator and Scientific Lead. Trial completed. Manuscript submitted. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Closed
Clinical Trial? Yes
Impact This trial is helping to define azacitidine based combination therapies. 
 
Title Roche RO504337 in Acute Leukaemia 
Description A Multi-center, Open-label, Phase I Study of Single Agent RO5045337 Administered Orally In patients with Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) In Blast Phase, Or Refractory Chronic Lymphocytic leukemia/Small Cell Lymphocytic Lymphoma (CLL/SCLL). Vyas was local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 623870
Impact Phase II trials started. 
 
Title UK AML NCRI Working Group AML 17, AML 18, AML 19 and LI1. 
Description Phase III UK AML trials: AML 19, LI1. Vyas is Lead for Genome England Program and flow cytometric leukaemic stem cell MRD studies. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier AML 17 - 55675535 , AML18 - 31682779 , AMl 19 78449203 , LI1 18218
Impact PV to write