Anti-CD47 antibody therapy in relapsed/refractory Haematological Malignancies
| ISRCTN | ISRCTN28039294 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN28039294 |
| EudraCT/CTIS number | 2015-000720-29 |
| ClinicalTrials.gov number | NCT02678338 |
| Secondary identifying numbers | CPMS 18953 |
- Submission date
- 14/05/2015
- Registration date
- 14/05/2015
- Last edited
- 25/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Contact information
Mr Tom Holmes
Public
Public
University of Oxford
Department of Oncology
Oncology Clinical Trials Office (OCTO)
Old Road Campus Research Building
Roosevelt Drive
Oxford
OX3 7DQ
United Kingdom
Study information
| Study design | Non-randomized; Interventional; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A Phase I dose escalation trial of the Humanized Anti-CD47 Monoclonal Antibody Hu5F9-G4 in Haematological Malignancies |
| Study acronym | CAMELLIA |
| Study hypothesis | Current study hypothesis: The aim of this study is to determine whether a new drug, called Hu5F9-G4, is a safe and well tolerated treatment for patients with Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS), whose disease has either not responded to standard treatments or has relapsed following an initial response. There is an urgent need for new treatments for these patients, who currently only receive supportive care and have a median survival of only 2 months. Previous study hypothesis: The aim of this study is to determine whether a new drug, called Hu5F9-G4, is a safe and well tolerated treatment for patients with Acute Myeloid Leukaemia (AML), whose disease has either not responded to standard treatments or has relapsed following an initial response. There is an urgent need for new treatments for these patients, who currently only receive supportive care and have a median survival of only 2 months. |
| Ethics approval(s) | South Central- Oxford C’, 14/05/2015, ref: 15/SC/0215 |
| Condition | Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (acute myeloid) and Myelodysplastic syndrome (MDS) |
| Intervention | All patients will receive the trial drug Hu5F9-G4, there is no control arm. Hu5F9-G4 is given as an intravenous infusion once or twice a week. The trial is of a dose escalation design. Patients who respond to the first 4 weeks of treatment will have the option of continuing treatment for a further 8 weeks i.e. up to 12 weeks in total. There is also allowance for patients to continue on treatment for a further 40 weeks (i.e. up to 1 year in total). (added 16/08/2016) Added 26/10/2017: If patients are still benefiting from treatment, they may have the option to continue on trial treatment until 52 weeks after the last patient has been recruited. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Phase I |
| Drug / device / biological / vaccine name(s) | Hu5F9-G4 |
| Primary outcome measure | Maximum tolerated dosing regimen of Hu5F9-G4; Timepoint(s): Over 4 weeks of treatment |
| Secondary outcome measures | Current as of 26/10/2017: 1. CD47 receptor occupancy; Timepoint(s): Days 1, 8, 11, 15, 18, 25, 36, 53, 64, 81 and weeks 16, 28, 40, 52 and every 12 weeks beyond week 52, 30-35 days post end of treatment, and disease progression 2. Immunogenicity of Hu5F9-G4; Timepoint(s): Days 1, 29, 53 and 81, and weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 every 4 weeks beyond week 52 and at 30-35 days post end of treatment. 3. Impact of blood transfusion on Hu5F9-G4 pharmacokinetics; Timepoint(s): Timings as per PK sampling. 4. Pharmacokinetic profile of Hu5F9-G4; Timepoint(s): Days 1,4, 8, 11, 15, 22, 25, 36, 50, 64, 78, and Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52 and every 4 weeks beyond week 52. 5. Preliminary evidence of anti-leukaemic/myelodysplastic activity of Hu5F9-G4; Timepoint(s): Days 25, 53, 81, and weeks 16, 28, 40 and 52 and every 12 weeks beyond week 52. 6. Safety of extending treatment duration: From week 5 until 30-35 day post end of treatment. As of 02/08/2017: 1. CD47 receptor occupancy; Timepoint(s): Days 1, 8, 11, 15, 18, 25, 36, 53, 64, 81 and weeks 16, 28, 40, 52 and disease progression 2. Immunogenicity of Hu5F9-G4; Timepoint(s): Days 1, 29, 53 and 81, and weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 3. Impact of blood transfusion on Hu5F9-G4 pharmacokinetics; Timepoint(s): Days 1,4, 8, 11, 15, 22, 25, 36, 50, 64, 78, and Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52 4. Pharmacokinetic profile of Hu5F9-G4; Timepoint(s): Days 1,4, 8, 11, 15, 22, 25, 36, 50, 64, 78, and Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52 5. Preliminary evidence of anti-leukaemic/myelodysplastic activity of Hu5F9-G4; Timepoint(s): Days 25, 53, 81, and weeks 16, 28, 40 and 52 6. Safety of extending treatment duration to 1 year; Timepoint(s): Weeks 5- 52 of treatment As of 16/08/2016: 1. CD47 receptor occupancy; Timepoint(s): Days 1, 8, 15, 22, 36, 53, 64, 81 and weeks 16, 28, 40, 52 and disease progression 2. Immunogenicity of Hu5F9-G4; Timepoint(s): Days 1, 29, 53 and 81, and weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 3. Impact of blood transfusion on Hu5F9-G4 pharmacokinetics; Timepoint(s): Days 1,4, 8, 15, 22, 25, 36, 50, 64, 78, and Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52 4. Pharmacokinetic profile of Hu5F9-G4; Timepoint(s): Days 1,4, 8, 15, 22, 25, 36, 50, 64, 78, and Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48 & 52 5. Preliminary evidence of anti-leukaemic activity of Hu5F9-G4; Timepoint(s): Days 25, 53, 81, and weeks 16, 28, 40 and 52 6. Safety of extending treatment duration to 1 year; Timepoint(s): Weeks 5- 52 of treatment Initial: 1. CD47 receptor occupancy; Timepoint(s): Days 1, 8, 15, 22, 36, 53, 64, 81 and at disease progression 2. Immunogenicity of Hu5F9-G4; Timepoint(s): Days 1, 29, 53 & 81 (if positive repeat assay every 4 weeks until no longer positive) 3. Impact of blood transfusion on Hu5F9-G4 pharmacokinetics; Timepoint(s): Days 1, 4, 8, 15, 22, 25, 36, 50, 64 & 78 4. Pharmacokinetic profile of Hu5F9-G4; Timepoint(s): Days 1,4, 8, 15, 22, 25, 36, 50, 64 & 78 5. Preliminary evidence of anti-leukaemic activity of Hu5F9-G4; Timepoint(s): Days 25, 53 & 81 (per International Working Group AML response criteria (2003)) 6. Safety of extending treatment duration to 12 weeks; Timepoint(s): Weeks 5-12 of treatment |
| Overall study start date | 15/10/2015 |
| Overall study end date | 07/06/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 30; UK Sample Size: 40 |
| Total final enrolment | 19 |
| Participant inclusion criteria | Current inclusion criteria as of 26/10/2017: 1. Pathologically confirmed relapsed or refractory (primary refractory and relapsed refractory) AML (defined by WHO criteria) for which no further conventional therapy is suitable for the patient; or confirmed myelodysplastic syndrome defined according to WHO classification, with an International Prognostic Scoring System (IPSS) risk category of intermediate-2 or high risk, that is relapsed, refractory or intolerant to conventional therapy within 3 weeks of registration. 2. Peripheral white blood cell (WBC) count ≤20x109/L within 1 week of registration (Day -7 to Day 1). Patients with WBC >20x109/L can be treated with hydroxyurea (up to 4 g/day) throughout the trial to reduce the WBC to ≤20x109/L prior to each dose of IMP. The white count must also be measured on the day of the first dose and be ≤20x109/L. Oral etoposide (up to 200mg PO/ day) may be given as an alternative to hydroxyurea for patients who are intolerant to hydroxyurea or cannot achieve sufficient white count lowering on hydroxyurea. 3. Male or female, Age >= 18 years 4. ECOG performance score of 01 5. Willing and able to comply with the protocol for the duration of the study, and scheduled followup visits and examinations 6. Willing to undergo blood transfusions as deemed clinically necessary 7. Pretreatment blood cross match completed 8. Written (signed and dated) informed consent and be capable of cooperating with protocol 9. Biochemical indices within the ranges shown below: 9.1. AST/SGOT or ALT/SGPT = 3 x ULN 9.2. Alkaline phosphatase = 2 x ULN 9.3. Bilirubin = 2x ULN (except for patients with a known or suspected history of Gilbert’s Syndrome) 9.4. eGFR >35 mls/min (Cockcroft and Galton method) Current inclusion criteria as of 02/08/2017: 1. Pathologically confirmed relapsed or refractory (primary refractory and relapsed refractory) AML (defined by WHO criteria) for which no further conventional therapy is suitable for the patient; or confirmed myelodysplastic syndrome defined according to WHO classification, with an International Prognostic Scoring System (IPSS) risk category of intermediate-2 or high risk, that is relapsed, refractory or intolerant to conventional therapy within 3 weeks of registration. 2. Peripheral white blood cell (WBC) count ≤20x109/L within 1 week of registration (Day -7 to Day 1). Patients with WBC >20x109/L can be treated with hydroxyurea (up to 4 g/day) throughout the trial to reduce the WBC to ≤20x109/L prior to each dose of IMP. The white count must also be measured on the day of the first dose and be ≤20x109/L. Oral etoposide (up to 200mg PO/ day) may be given as an alternative to hydroxyurea for patients who are intolerant to hydroxyurea or cannot achieve sufficient white count lowering on hydroxyurea. 3. Male or female, Age >= 18 years 4. ECOG performance score of 01 5. Willing and able to comply with the protocol for the duration of the study, and scheduled followup visits and examinations 6. Willing to undergo blood transfusions as deemed clinically necessary 7. Pretreatment blood cross match completed 8. Written (signed and dated) informed consent and be capable of cooperating with protocol 9. Haematological and biochemical indices within the ranges shown below: 9.1. AST/SGOT or ALT/SGPT = 3 x ULN 9.2. Alkaline phosphatase = 2 x ULN 9.3. Bilirubin = 2x ULN (except for patients with a known or suspected history of Gilbert’s Syndrome) 9.4. eGFR >35 mls/min (Cockcroft and Galton method) Previous inclusion criteria: 1. Pathologically confirmed relapsed or refractory (primary refractory and relapsed refractory) AML (defined by WHO criteria) for which no further conventional therapy is suitable for the patient within 3 weeks of registration 2. Peripheral white blood cell (WBC) count =10x10*9/L within 1 week of registration (Day 7 to Day 1). Patients with WBC >10x10*9/L can be treated with hydroxycarbamide (up to 4 g/day) throughout the trial to reduce the WBC to =10x10*9/L prior to each dose of IMP. The white count must also be measured on the day of the first dose and be =10x10*9/L prior to each dose of IMP. The white count must also be measured on the day of the first dose and be =10x10*9/L 3. Male or female, Age >= 18 years 4. ECOG performance score of 01 5. Willing and able to comply with the protocol for the duration of the study, and scheduled followup visits and examinations 6. Willing to undergo blood transfusions as deemed clinically necessary 7. Pretreatment blood cross match completed 8. Written (signed and dated) informed consent and be capable of cooperating with protocol 9. Haematological and biochemical indices within the ranges shown below: 9.1. AST/SGOT or ALT/SGPT = 3 x ULN 9.2. Alkaline phosphatase = 2 x ULN 9.3. Bilirubin = 2x ULN (except for patients with a known or suspected history of Gilbert’s Syndrome) 9.4. eGFR >35 mls/min (Cockcroft and Galton method) |
| Participant exclusion criteria | Current exclusion criteria as of 26/10/2017: 1. Females: Pregnant or breastfeeding women, or women of childbearing potential unless effective method of contraception is used during and for 3 months after the trial. Males: unless an effective method of contraception is used during and for 3 months after the trial 2. Any prior exposure to Hu5F9G4 or other CD47 targeting agent 3. Treatment with any other investigational agent within 28 days prior to enrolment 4. Prior cytotoxic chemotherapy (with the exception of hydroxycarbamide), immunotherapy, or radiotherapy within 4 weeks prior to Day 1 5. Acute Promyelocytic Leukaemia 6. Patients with known inherited or acquired bleeding disorders 7. Previous allogeneic haematopoietic stem cell transplant within 6 months prior to enrollment, active graft versus host disease (GVHD), or requiring transplant-related immunosuppression 8. Evidence for active CNS involvement by leukaemia 9. Clinical evidence or known history of cardiopulmonary disease defined as follows: 9.1. Acute myocardial infarction within the last 12 months 9.2. Requirement for treatment of angina or existence of unstable angina 9.3. Congestive heart failure NYHA Class II–IV 9.4. Uncontrolled hypertension despite adequate treatmen 10. Symptomatic intrinsic lung disease (chronic obstructive pulmonary disease, pulmonary fibrosis) 11. Other psychological, social or medical condition (e.g. active severe sepsis) physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results 12. Any other malignancy within the previous 24 months, with the exception of adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin 13. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV Current exclusion criteria as of 02/08/2017: 1. Females: Pregnant or breastfeeding women, or women of childbearing potential unless effective method of contraception is used during and for 3 months after the trial. Males: unless an effective method of contraception is used during and for 3 months after the trial 2. Any prior exposure to Hu5F9G4 or other CD47 targeting agent 3. Treatment with any other investigational agent within 28 days prior to enrolment 4. Prior cytotoxic chemotherapy (with the exception of hydroxycarbamide), immunotherapy, or radiotherapy within 4 weeks prior to Day 1 5. Acute Promyelocytic Leukaemia 6. Patients with known inherited or acquired bleeding disorders 7. Previous allogeneic haematopoietic stem cell transplant within 6 months prior to enrollment, active graft versus host disease (GVHD), or requiring transplant-related immunosuppression 8. Evidence for active CNS involvement by leukaemia 9. Clinical evidence or known history of cardiopulmonary disease defined as follows: 9.1. Acute myocardial infarction within the last 12 months 9.2. Requirement for treatment of angina or existence of unstable angina 9.3. Congestive heart failure NYHA Class II–IV 9.4. Uncontrolled hypertension despite adequate treatment (sustained systolic BP > 150 or diastolic BP > 100) 10. Symptomatic intrinsic lung disease (chronic obstructive pulmonary disease, pulmonary fibrosis) 11. Other psychological, social or medical condition (e.g. active severe sepsis) physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results 12. Any other malignancy within the previous 24 months, with the exception of adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin 13. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV Previous exclusion criteria: 1. Females: Pregnant or breastfeeding women, or women of childbearing potential unless effective method of contraception is used during and for 3 months after the trial. Males: unless an effective method of contraception is used during and for 3 months after the trial 2. Any prior exposure to Hu5F9G4 or other CD47 targeting agent 3. Treatment with any other investigational agent within 28 days prior to enrolment 4. Prior cytotoxic chemotherapy (with the exception of hydroxycarbamide), immunotherapy, or radiotherapy within 4 weeks prior to Day 1 5. Acute Promyelocytic Leukaemia 6. Patients with known inherited or acquired bleeding disorders 7. Previous allogeneic stem cell transplant 8. Evidence for active CNS involvement by leukaemia 9. Clinical evidence or known history of cardiopulmonary disease defined as follows: 9.1. Acute myocardial infarction within the last 12 months 9.2. Requirement for treatment of angina or existence of unstable angina 9.3. Congestive heart failure NYHA Class II–IV 9.4. Uncontrolled hypertension despite adequate treatment sustained systolic BP > 150 or diastolic BP > 100) 10. Symptomatic intrinsic lung disease (chronic obstructive pulmonary disease, pulmonary fibrosis) 11. Other psychological, social or medical condition (e.g. active severe sepsis) physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results 12. Any other malignancy within the previous 24 months, with the exception of adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin 13. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV |
| Recruitment start date | 27/11/2015 |
| Recruitment end date | 07/06/2018 |
Locations
Countries of recruitment
- England
- United Kingdom
- Wales
Study participating centres
Churchill Hospital (lead site)
Oxford
OX3 7LJ
United Kingdom
OX3 7LJ
United Kingdom
Christie Hospital
Manchester
M20 4BX
United Kingdom
M20 4BX
United Kingdom
Royal Liverpool Hospital
Liverpool
L7 8XP
United Kingdom
L7 8XP
United Kingdom
St James Hospital
Leeds
LS9 7TF
United Kingdom
LS9 7TF
United Kingdom
University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom
CF14 4XW
United Kingdom
Sponsor information
Forty Seven, Inc.
Industry
Industry
1490 O’Brien Drive, Suite A
Menlo Park
California
94304
United States of America
| Website | http://www.fortyseveninc.com/ |
|---|
Funders
Funder type
Charity
Bloodwise
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Medical Research Council
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
NIHR Oxford Biomedical Research Centre (BRC)
No information available
CRUK Cancer Centre
No information available
California Institute for Regenerative Medicine
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- California Institute for Regenerative Med, CA Institute for Regenerative Med, California's Stem Cell Agency, CIRM
- Location
- United States of America
Results and Publications
| Intention to publish date | |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | Results of this trial will be submitted for publication in a peer‐reviewed journal. All presentations and publications will be pre‐agreed by the Combined Anti‐CD47 Clinical Trial Steering Committee (CTSC). |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 01/07/2019 | 09/08/2019 | Yes | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Plain English results | 25/06/2024 | No | Yes |
Editorial Notes
25/06/2024: Cancer Research UK plain English results added.
21/01/2020: Internal review.
09/08/2019: The following changes were made to the trial record:
1. Publication reference added.
2. The total final enrolment was added.
01/03/2019: Internal review.
03/08/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/03/2018 to 07/06/2018.
2. The overall trial end date was changed from 28/02/2019 to 07/06/2019.
20/02/2018: The study contact Hannah Johnson was removed and Tom Holmes has been added. The recruitment end date has been updated from 31/01/2018 to 31/03/2018.
26/10/2017: The public title has been changed from "Anti-CD47 antibody therapy in relapsed/refractory AML" to "Anti-CD47 antibody therapy in relapsed/refractory Haematological Malignancies". The interventions and outcome measures have been updated. The inclusion and exclusion criteria has been updated.
02/08/2017: The scientific title has been updated from "A Phase I dose escalation trial of the humanized anti-CD47 monoclonal antibody Hu5F9-G4 in acute myeloid leukaemia" to "A Phase I dose escalation trial of the Humanized Anti-CD47 Monoclonal Antibody Hu5F9-G4 in Haematological Malignancies". Myelodysplastic syndrome (MDS) has been added as a condition. Mrs Helen Flight has been removed and replaced with Ms Hannah Johnson. The overall trial end date has been updated from 31/12/2017 to 28/02/2019. The recruitment dates have been updated from 15/10/2015-15/04/2017 to 27/11/2015-31/01/2018. The target enrolment date has been updated from 30 to 40. ClinicalTrials.gov number has been added. St Bartholomew’s Hospital and City Hospital Nottingham have been removed as trial participating sites. The Virginia and D.K. Ludwig Fund for Cancer Research has been removed as a funder.
16/08/2016: Slight amendment made to intervention (date stamped in field), added amended secondary outcome measures. Changed sponsor contact details. Removed following exclusion criteria: Prior splenectomy. Removed Queen Elizabeth Hospital (London) from list of trial participating centres
23/06/2016: Changed sponsor from Stanford University to Forty seven Inc. Updated funder name from Leukaemia and Lymphoma Research to Bloodwise
29/02/2016: Cancer Help UK lay summary link added.
08/09/2015: Updated overall trial start date, and recruitment start date from 01/07/2015 to 15/10/2015. Changed recruitment end date to 15/04/2017 to 31/12/2017. Five additional funders added.
