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The purpose of this study is to assess the safety and efficacy of infusing natural killer cells from a donor as treatment for patients with acute myeloid leukemia in remission or who have experienced relapse.
Natural killer (NK) cells extracted from a [parental] donor are infused intravenously. Most patients are given a multi-agent chemotherapeutic conditioning regimen prior to the infusion. The conditioning regimen may be omitted for patients who have previously received traditional stem cell transplant.
Details of Treatment Plan:
Stratum 1 (AML in complete remission)
Cyclophosphamide 60 mg/kg IV Day -7 Fludarabine 25 mg/m2/day IV Days -6 through -2 Donor pheresis Day -1 Start IL-2 on Day -1, then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0
Stratum 2 (AML that is refractory or relapsed or AML with increasing minimal residual disease)
Clofarabine 40 mg/m2 IV, days -6 through -2 Etoposide 100 mg/m2 IV, days -6 through -2 Cyclophosphamide 400 mg/m2 IV, days -6 through 02 Donor pheresis Day -1 Start IL-2 Day -1, and then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0.
For patients who have received prior SCT, the conditioning regimen may be omitted if the NK cells are obtained from the original SCT donor.
Cytokine regimen (stratum 1 and 2): 1 million units/m2 of IL-2 given subcutaneously three times per week for two weeks (6 doses) starting on the evening of day -1.
NK Cell Transplantation (stratum 1 and 2): NK cells from haplo-identical family donor will be infused on day 0.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stratum 1 | Experimental | Stratum 1 (AML in complete remission) Cyclophosphamide 60 mg/kg IV Day -7 Fludarabine 25 mg/m2/day IV Days -6 through -2 Donor pheresis Day -1 Start IL-2 on Day -1, then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0 |
|
| Stratum 2 | Experimental | Stratum 2 (AML that is refractory or relapsed or AML with increasing minimal residual disease) Clofarabine 40 mg/m2 IV, days -6 through -2 Etoposide 100 mg/m2 IV, days -6 through -2 Cyclophosphamide 400 mg/m2 IV, days -6 through 02 Donor pheresis Day -1 Start IL-2 Day -1, and then 3 times per week x 2 weeks NK Cell purification and infusion on Day 0. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cyclophosphamide, Fludarabine, Clofarabine, Etoposide, Interleukin-2 | Drug | See Detailed Description section for additional details of treatment interventions. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Document the number of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria. | Beginning at on therapy through 100 days post-transplant |
| Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Document the proportion of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria. | Beginning at on therapy through 100 days post-transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Duration of Engraftment of Natural Killer (NK) Cells | NK cell engraftment defined as NK cell chimerism in recipients. | Measured at days 2, 7, 14, 21 and 28 after NK cell transplantation, and up to 189 days post transplant as clinically indicated |
| Percent of Peak NK Cell Chimerism |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jeffrey E. Rubnitz, M.D. | St. Jude Children's Research Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Jude Children's Research Hospital | Memphis | Tennessee | 38105 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20085940 | Result | Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, Pui CH, Leung W. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol. 2010 Feb 20;28(6):955-9. doi: 10.1200/JCO.2009.24.4590. Epub 2010 Jan 19. |
| Label | URL |
|---|---|
| St. Jude Children's Research Hospital | View source |
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49 participants were enrolled on the study. This report is based on results for 25 patients. 24 were donors and were excluded. All analyses are based on the intent-to-treat principle and therefore include all recipients with data available for the reported endpoint.
49 participants were recruited between October 2005 and October 2011.
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | Participants with AML in complete remission (stratum 1). AML in complete remission is defined as trilineage hematopoietic recovery with less than 5% blasts in the marrow. Arm 1 participants received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. |
| FG001 | Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled prior to Amendment 2.0 received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. |
| FG002 | Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled after protocol Amendment 2.0 received a novel conditioning regimen of clofarabine, etoposide and cyclophosphamide prior to NK cell transplantation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | AML in complete remission (stratum 1). AML in complete remission is defined as trilineage hematopoietic recovery with less than 5% blasts in the marrow. Arm 1 participants received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Document the number of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria. | Grade 3 and 4 toxicities were assessed using Common Toxicity Criteria V.3.0 The assessment period was from the date on therapy through 100 days post-transplant. | Posted | Number | participants | Beginning at on therapy through 100 days post-transplant |
|
Beginning at on therapy through 100 days post-transplant
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm 1: Conditioning Regimen: Cyclophosphamide/Fludarabine | AML in complete remission (stratum 1). AML in complete remission is defined as trilineage hematopoietic recovery with less than 5% blasts in the marrow. Participants received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neutrophils/granulocytes (ANC/AGC) | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hemoglobin | Blood and lymphatic system disorders | CTCAE (3.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jeffrey Rubnitz, MD | St. Jude Children's Research Hospital | 1-866-278-5833 | info@stjude.org |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D007938 | Leukemia |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D003520 | Cyclophosphamide |
| C024352 | fludarabine |
| D000077866 | Clofarabine |
| D005047 | Etoposide |
| D007376 | Interleukin-2 |
| ID | Term |
|---|---|
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
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| Natural Killer Cell Infusion | Procedure | See Detailed Description section for additional details of treatment interventions. |
|
| CliniMACS System | Device | See Detailed Description section for additional details of treatment interventions. |
|
The maximum percent of donor NK cell in recipients during a four-week period after NK cell infusion. |
| Days 2, 7, 14, 21 and 28 after NK cell transplantation |
| Percent of Detectable Donor NK Cells at Day 28 | The percent of detectable donor NK cells in recipients at 28 days after NK cell infusion. Three of 10 participants had detectable donor cells at week 4. The results report the percent of detectable cells in the 3 participants. | At 28 days |
| Day That Maximum NK Cell Engraftment Was Reached | The time elapsed after transplantation in days until peak KIR-mismatched donor NK cell expansion was reached in recipients | Day 0 through Day 28 post NK cell transplantation |
| Number of KIR-mismatched NK Cells | Number of KIR-mismatched donor NK cells in recipients' blood at day 2 and day 14 post NK cell infusion. | Day 2 and day 14 post NK cell transplantation |
| Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562) | NK cells in recipient achieving ability to lyse target cell line (K562) within normal range established by donor NK cells. | Days 2, 7, 14, 21, and 28 after NK cell transplantation |
| Relapse-free Survival | For Arm 1, the efficacy of NK cell transplantation will be reported as the proportion of participants who achieve complete or partial remission. Kaplan-Meier estimates of relapse-free survival and confidence interval was determined by binomial distribution because no events were observed. The binomial interval is based on the number of patients at risk. | Up to 2 years post NK cell transplantation |
| Overall Survival | Overall survival is defined as the time relapse from on study date to death with those alive at last follow up date censored. The Kaplan-Meier method was used to compute survival probability estimates and confidence interval was determined by binomial distribution (for no events or all events) or by log hazard method. The binomial interval is based on the number of patients at risk. The confidence intervals for Arm 1 and Arm 2a were determined by binomial distribution. The confidence interval for Arm 2b was determined by log hazard method. | Up to 2 years post NK cell transplantation |
| BG001 |
| Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine |
AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled prior to Amendment 2.0 received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. |
| BG002 | Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled after protocol Amendment 2.0 received a novel conditioning regimen of clofarabine, etoposide and cyclophosphamide prior to NK cell transplantation. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG001 | Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD). Participants enrolled prior to Amendment 2.0 received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. Refractory: ≥ 20% leukemic blasts in the bone marrow or no decrease in the percentage of blasts in the bone marrow (e.g., if a patient starts with 15% blasts and still has 15% blasts, he would have refractory disease). Relapse: presence of ≥ 20% leukemic blasts in the bone marrow or the development of extramedullary disease after CR is achieved. Increasing Minimal Residual Disease (MRD) indicates higher MRD levels. |
| OG002 | Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled after protocol Amendment 2 received a novel conditioning regimen of clofarabine, etoposide and cyclophosphamide prior to NK cell transplantation. |
|
|
| Primary | Proportion of Patients Experiencing Grade 3 or 4 Toxicities During Conditioning and up to 100 Days Post-transplant | Document the proportion of patients experiencing grade 3 or 4 toxicities during conditioning and up to 100 days post-transplant. Toxicities were identified using Common Toxicity Criteria V 3.0 criteria. | Grade 3 and 4 toxicities were assessed using Common Toxicity Criteria V.3.0 The assessment period was from the date on therapy through 100 days post-transplant. | Posted | Number | proportion of patients | Beginning at on therapy through 100 days post-transplant |
|
|
|
| Secondary | Duration of Engraftment of Natural Killer (NK) Cells | NK cell engraftment defined as NK cell chimerism in recipients. | Arm 2 participants were not analyzed for this outcome as many of these patients proceeded to allogeneic stem cell transplantation following NK cell transplantation. | Posted | Median | Full Range | Days | Measured at days 2, 7, 14, 21 and 28 after NK cell transplantation, and up to 189 days post transplant as clinically indicated |
|
|
|
| Secondary | Percent of Peak NK Cell Chimerism | The maximum percent of donor NK cell in recipients during a four-week period after NK cell infusion. | Arm 2 participants were not analyzed for this outcome as many of these patients proceeded to allogeneic stem cell transplantation following NK cell transplantation. | Posted | Median | Full Range | percent of NK cells | Days 2, 7, 14, 21 and 28 after NK cell transplantation |
|
|
|
| Secondary | Percent of Detectable Donor NK Cells at Day 28 | The percent of detectable donor NK cells in recipients at 28 days after NK cell infusion. Three of 10 participants had detectable donor cells at week 4. The results report the percent of detectable cells in the 3 participants. | Three of 10 participants continued to have detectable donor NK cells at week 4. | Posted | Median | Full Range | percent of donor NK cells | At 28 days |
|
|
|
| Secondary | Day That Maximum NK Cell Engraftment Was Reached | The time elapsed after transplantation in days until peak KIR-mismatched donor NK cell expansion was reached in recipients | Nine of the 10 participants in Arm 1 received KIR-mismatched NK donor cells. | Posted | Median | Full Range | number of days | Day 0 through Day 28 post NK cell transplantation |
|
|
|
| Secondary | Number of KIR-mismatched NK Cells | Number of KIR-mismatched donor NK cells in recipients' blood at day 2 and day 14 post NK cell infusion. | Nine of the 10 participants in Arm 1 received KIR-mismatched NK donor cells. | Posted | Median | Full Range | cells/µl | Day 2 and day 14 post NK cell transplantation |
|
|
|
| Secondary | Number of Participants With Evidence of NK Cells Lysing a Target Cell Line (K562) | NK cells in recipient achieving ability to lyse target cell line (K562) within normal range established by donor NK cells. | All 10 participants received NK donor cells; 9 of the 10 participants received KIR-mismatched NK donor cells. | Posted | Number | participants | Days 2, 7, 14, 21, and 28 after NK cell transplantation |
|
|
|
| Secondary | Relapse-free Survival | For Arm 1, the efficacy of NK cell transplantation will be reported as the proportion of participants who achieve complete or partial remission. Kaplan-Meier estimates of relapse-free survival and confidence interval was determined by binomial distribution because no events were observed. The binomial interval is based on the number of patients at risk. | Posted | Number | 95% Confidence Interval | Percent probability | Up to 2 years post NK cell transplantation |
|
|
|
| Secondary | Overall Survival | Overall survival is defined as the time relapse from on study date to death with those alive at last follow up date censored. The Kaplan-Meier method was used to compute survival probability estimates and confidence interval was determined by binomial distribution (for no events or all events) or by log hazard method. The binomial interval is based on the number of patients at risk. The confidence intervals for Arm 1 and Arm 2a were determined by binomial distribution. The confidence interval for Arm 2b was determined by log hazard method. | Posted | Number | 95% Confidence Interval | Percent probability | Up to 2 years post NK cell transplantation |
|
|
|
| 1 |
| 10 |
| 1 |
| 10 |
| EG001 | Arm 2a: Conditioning Regimen: Cyclophosphamide/Fludarabine | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD). Participants enrolled prior to Amendment 2.0 received a traditional conditioning regimen of cyclophosphamide and fludarabine prior to NK cell transplantation. Refractory: ≥ 20% leukemic blasts in the bone marrow or no decrease in the percentage of blasts in the bone marrow (e.g., if a patient starts with 15% blasts and still has 15% blasts, he would have refractory disease). Relapse: presence of ≥ 20% leukemic blasts in the bone marrow or the development of extramedullary disease after CR is achieved. Increasing Minimal Residual Disease (MRD) indicates higher MRD levels. | 0 | 3 | 3 | 3 |
| EG002 | Arm 2b: Conditioning: Clofarabine/Etoposide/Cyclophosphamide | AML that is refractory or relapsed or AML with increasing minimal residual disease (MRD) (stratum 2). Participants enrolled after protocol Amendment 2 received a novel conditioning regimen of clofarabine, etoposide and cyclophosphamide prior to NK cell transplantation. | 2 | 12 | 11 | 12 |
| Hypotension | Cardiac disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hepatobiliary/Pancreas - Other | Hepatobiliary disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, blood | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, Rectum | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Anorexia | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Colitis | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Typhlitis (cecal inflammation) | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hemorrhage, GI, Oral cavity | General disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hemorrhage, pulmonary/upper respiratory, Nose | General disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Hemorrhage/Bleeding - Other (Specify, __) | General disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Febrile neutropenia-fever of unknown origin without clinically or microbiologically documented infe | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection - Other (Specify, __) | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, Blood | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection with normal ANC or Grade 1 or 2 neutrophils, Blood | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| ALT, SGPT (serum glutamic pyruvic transaminase) | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Bilirubin (hyperbilirubinemia) | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Phosphate, serum-low (hypophosphatemia) | Metabolism and nutrition disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Cystitis | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Phosphate, serum-low (hypokalemia) | Renal and urinary disorders | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, Lip/perioral | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
| Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, Rectum | Infections and infestations | CTCAE (3.0) | Non-systematic Assessment |
|
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| D006425 |
| Hemic and Lymphatic Diseases |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D000227 | Adenine Nucleotides |
| D011685 | Purine Nucleotides |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D009711 | Nucleotides |
| D012265 | Ribonucleotides |
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D011083 | Polycyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |