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The Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blood Stem Cell Transplantation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05436418
Recruitment Status : Recruiting
First Posted : June 29, 2022
Last Update Posted : November 25, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Blood cancers (such as leukemias or lymphomas) often do not respond to standard treatments. A transplant of blood stem cells from a healthy donor can help people with these cancers. Sometimes these transplants cause serious side effects, including a common immunologic problem called graft-versus-host disease. A drug called cyclophosphamide given early after the transplant (post-transplantation cyclophosphamide, PTCy) can reduce these complications. But sometimes this drug has its own negative effects. Furthermore, studies in mice suggest that an intermediate, rather than very high, dose of this drug may best protect against graft-versus-host disease.

Objective:

To find out if a lower dose of PTCy is more helpful for people who undergo blood stem cell transplants.

Eligibility:

People aged 18 and older who have a blood cancer and are eligible for a transplant of blood stem cells from another person. Healthy donors are also needed but must be related to the individual needing the transplant.

Design:

Participants will undergo screening. Transplant recipients will have imaging scans and tests of their heart and lung function. They will be assessed for the status of their cancer, including bone marrow taken from their pelvis and possibly also scans and/or fluid drawn from the spine depending on the disease type.

Donors will be screened for general health. They will give several tubes of blood. They will give an oral swab and saliva and stool samples for research.

Recipients will be in the hospital at least 4 to 6 weeks.

They will have a temporary catheter inserted into a vein in the chest or neck. Medications will be given and blood will be drawn through the catheter.

The transplanted stem cells will be given through the catheter. Participants will receive medications both before and after the transplant.

Participants will return to the clinic at least once a week for 3 months after leaving the hospital. Follow-up visits will continue periodically for 5 years.


Condition or disease Intervention/treatment Phase
Peripheral Blood Stem Cell Transplantation Hematopoietic Stem Cell Transplantation Drug: Melphalan Drug: Sirolimus Radiation: Total Body Irradiation (TBI) Drug: Cyclophosphamide Drug: Mycophenolate Mofeti Drug: Fludarabine Procedure: Allogeneic HSCT Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial to Determine the Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blood Stem Cell Transplantation
Actual Study Start Date : November 18, 2022
Estimated Primary Completion Date : June 25, 2027
Estimated Study Completion Date : July 2, 2027


Arm Intervention/treatment
No Intervention: Donors (Haplo HCT)
Research on collected samples
No Intervention: Donors (Matched HCT)
Research on collected samples
Experimental: Phase I Dose De-escalation (Haplo HCT)
PTCy at de-escalating doses to assess for safety and determine Phase II dose
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant

Experimental: Phase I Dose De-escalation (Matched HCT)
PTCy at de-escalating doses to assess for safety and determine Phase II dose
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant

Experimental: Phase I Pilot for Comparative Data (Haplo HCT)
Standard PTCy 50 mg/kgday on days +3 and +4
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant

Experimental: Phase I Pilot for Comparative Data (Matched HCT)
Standard PTCy 50 mg/kg/day on days +3 and +4
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant

Experimental: Phase II Efficacy (Haplo HCT)
PTCy at shortest duration, safe dose (from Phase I)
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant

Experimental: Phase II Efficacy (Matched HCT)
PTCy at shortest duration, safe dose (from Phase I)
Drug: Melphalan
Matched HCT: 100 mg/m^2 IV on day -2 over 30 minutes. Haplo HCT: 100 mg/m^2 IV on day -6 over 30 minutes.

Drug: Sirolimus
Loading dose of 6 mg orally given on day +5 (calculated based on actual body weight, max initial dose 6 mg), then maintenance dose starting at 2 mg orally daily on day +6 with dose adjustments to maintain a trough of 5-12 ng/ml, continued through day +80 with no taper. Doses should be modified as appropriate for drug interactions.

Radiation: Total Body Irradiation (TBI)
Haplo HCT only: A dose of 200 cGy will be administered on day -1.

Drug: Cyclophosphamide
based on dose level being tested (50, 35, 25, or 15 mg/kg) IV once daily over 2 hours on days +3 and +4. Cyclophosphamide will be dosed according to ideal body weight. Cyclophosphamide infusion on days +3 should be started between 70-74 hours after the start of the PBSC infusion. Cyclophosphamide infusion on day +4 should be started between 94-98 hours after the start of the bone marrow infusion.

Drug: Mycophenolate Mofeti
15 mg/kg orally or IV three times daily (max 1000 mg/dose) starting on day +5, continued through day +35. Dosing will be according to actual body weight.

Drug: Fludarabine
Matched HCT: 25 mg/m^2/day infused IV over 60 minutes from day -7 to day -3. Haplo HCT: 30 mg/m^2/day infused IV over 60 minutes from day -5 to day -2

Procedure: Allogeneic HSCT
Stem cell transplant




Primary Outcome Measures :
  1. Phase II: Evaluate the efficacy of PTCy, at the lowest dose determined for each HLA-matching arm from phase I, as assessed by 1-year GVHD-free relapse-free survival (GRFS) rate. [ Time Frame: 1 year ]
    1-year GRFS and 95% CI per arm will be estimated using Kaplan-Meier curves.

  2. Phase I: Determine the lowest effective dose of PTCy in combination with sirolimus and mycophenolate mofetil as GVHD prophylaxis after reduced intensity conditioning and PBSCT, as assessed by primary graft failure AND Grade III-IV acute GVHD as ... [ Time Frame: 60 days ]
    Number of evaluable subjects and DLT will be summarized per dose level in each arm.


Secondary Outcome Measures :
  1. Estimate rates of symptomatic BK virus cystitis. (Phase I and II) [ Time Frame: 100 days ]
    To evaluate symptomatic BK virus cystitis using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing the outcome.

  2. Estimate rates of hematopoietic recovery/engraftment. (Phase I and II) [ Time Frame: day 28, 42, and 100 ]
    Rate and timing of neutrophil and platelet engraftment also will be evaluated descriptively, including fractions who attain each condition at day 28, 42, and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting subjects.

  3. Estimate rates of Grade II-IV and III-IV acute GVHD at 100 days (Phase I and II) [ Time Frame: 100 days ]
    To evaluate for grades II-IV and III-IV acute GVHD at 100 days using Kaplan-Meier curves or competing risk-based cumulative incidence curves. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.

  4. Estimate non-relapse mortality at one year (Phase II only) [ Time Frame: 1 year ]
    To evaluate non-relapse mortality at one year, estimates will be determined using competing risk-based cumulative incidence curves. Relapse and non-relapse mortality will be competing risks for each other.

  5. Estimate overall survival and progression-free survival at one year (Phase II only) [ Time Frame: 1 year ]
    To evaluate survival at one year, estimates will be determined using Kaplan-Meier curves.

  6. Estimate incidence progression/relapse at one year (Phase II only) [ Time Frame: 1 year ]
    To evaluate relapse at one year, estimates will be determined using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Relapse and non-relapse mortality will be competing risks for each other.

  7. Describe and characterize cytokine release syndrome (CRS) (Phase I and II) [ Time Frame: 1 year ]
    To evaluate CRS incidence, frequency and severity using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Relapse/progression and NRM will be competing risks.

  8. Estimate rates of CMV reactivation requiring preemptive therapy. (Phase I and II) [ Time Frame: 100 days ]
    To evaluate CMV reactivation requiring preemptive therapy using Kaplan-Meier curves or competing risk-based cumulative incidence curves as appropriate. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.

  9. Estimate rates of any chronic GVHD and moderate/severe chronic GVHD at one year (Phase I and II) [ Time Frame: 1 year ]
    To evaluate for all chronic and moderate/severe chronic GVHD at one year using Kaplan-Meier curves or competing risk-based cumulative incidence curves. Competing risks will include relapse/progression and NRM. For phase I, these analyses will be presented descriptively or as proportions of subjects experiencing an outcome.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

Recipient

  • Participants must have a histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation limited to one of the following:

    • Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission (<5% blasts in the bone marrow, no detectable abnormal peripheral blasts, and no extramedullary disease)
    • AML of any risk in second or subsequent morphologic complete remission
    • Acute lymphoblastic leukemia in first or subsequent complete remission
    • Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)
    • Primary myelofibrosis of intermediate-2 or higher risk by the DIPSS
    • Chronic myelomonocytic leukemia
    • Chronic myelogenous leukemia resistant to or intolerant of >= 3 tyrosine kinase inhibitors or with history of accelerated phase or blast crisis
    • B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment, relapsed after autologous transplantation, or has progressed through at least 2 lines of therapy
    • Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors
    • Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines
    • Hematologic malignancy of dendritic cell or histiocytic cell type
    • Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)
  • Age >= 50 years or age 18-49 years and also meeting one of the following criteria:

    • Prior myeloablative HCT
    • Prior exposure to inotuzumab, gemtuzumab, or other agent that increases the risk for sinusoidal obstruction syndrome.
    • Hematopoietic Cell Transplantation- Comorbidity Index (HCT-CI) >= 3
    • Karnofsky performance score <80
    • Co-morbidity considered by the treating physician to be exclusionary of myeloablative conditioning
  • At least one potentially suitable HLA-haploidentical or 10/10 (HLA-A, B, C, DR, DQ) related or unrelated donor for HCT
  • Karnofsky performance score >= 70
  • Adequate organ function defined as possessing all of the following:

    • Cardiac ejection fraction >= 45% by 2D ECHO;
    • Forced expiratory volume-1 (FEV-1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) all of >= 50% predicted;
    • Estimated serum creatinine clearance of >= 60 ml/minute/1.73m^2 calculated using eGFR in the clinical lab;
    • Total bilirubin <= 2X the upper limit of normal;
    • Alanine aminotransferase and aspartate aminotransferase <= 3X the upper limit of normal.
  • Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one year post-transplant.
  • WOCBP must have a negative serum or urine pregnancy test within 7 days prior to initiation of conditioning regimen.
  • Ability of participant to understand and the willingness to sign a written informed consent document.

Donor

  • Related donor (age >= 12) deemed suitable and eligible, and willing to donate, per clinical evaluations, who are additionally willing to donate blood, saliva, oral swab, and stool for research. Related donors will be evaluated in accordance with existing institutional Standard Policies and Procedures for determination of eligibility and suitability for clinical donation.
  • Ability of participant or parent/legal guardian to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Recipient

  • Participants who are receiving any other investigational agents. Prior experimental therapies must have been completed at least 2 weeks prior to the date of beginning conditioning.
  • Active breastfeeding.
  • Active malignancy of non-hematopoietic type (excluding non-melanoma skin cancers) which is: metastatic, or relapsed/refractory to treatment, or locally advanced and not amenable to curative treatment, or limited disease treated with curative intent treatment within the last 2 years. This excludes non-melanoma skin cancers.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents.
  • Uncontrolled intercurrent illness (e.g., severe endocrinopathy, disseminated intravascular coagulation, profound electrolyte disturbance, active infectious hepatitis, uncontrolled dental infection) that in the opinion of the Site PI would make it unsafe to proceed with transplantation.

Donor

None


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05436418


Contacts
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Contact: Amy H Chai (301) 219-7105 amy.chai@nih.gov
Contact: Christopher G Kanakry, M.D. (240) 760-6171 christopher.kanakry@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Christopher G Kanakry, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05436418    
Other Study ID Numbers: 10000613
000613-C
First Posted: June 29, 2022    Key Record Dates
Last Update Posted: November 25, 2022
Last Verified: November 22, 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Reduced Intensity Conditioning
Systemic Immunosuppressive Therapy
Hematologic Malignancy
Acute Myeloid Leukemia
Calcineurin Inhibitor
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Sirolimus
Cyclophosphamide
Melphalan
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents