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A Study of Melphalan, BCNU, Vitamin B12b, Vitamin C, and Stem Cell Infusion in People With Advanced Pancreatic Cancer and BRCA Mutations

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: NCT04150042
Recruitment Status : Recruiting
First Posted : November 4, 2019
Last Update Posted : March 29, 2022
Sponsor:
Information provided by (Responsible Party):
General Oncology, Inc.

Brief Summary:
The clinical trial is a phase 1, single-arm trial that will evaluate the safety of the investigational treatment on pancreatic cancer in patients who have an inherited, deleterious BRCA1 or BRCA2 genetic alteration. The investigational treatment will involve 2 cycles of a combination of intravenous melphalan, BCNU, low-dose I.V. ethanol, vitamin B12b, and vitamin C in association with autologous hematopoietic stem cell infusion. A dose-escalation schedule will be employed for vitamin C

Condition or disease Intervention/treatment Phase
Pancreatic Adenocarcinoma Metastatic BRCA1 Mutation BRCA2 Mutation Drug: Melphalan Drug: BCNU Drug: Vitamin B12B Drug: Vitamin C Drug: Ethanol Device: Autologous Hematopoietic Stem Cells Phase 1

Detailed Description:

In the current clinical trial, participants with BRCA-related metastatic pancreatic cancer will receive a combination of melphalan, BCNU, low-dose ethanol, vitamin B12b, and vitamin C in conjunction with autologous stem cell infusion. The drug combination is designed to address multiple mechanisms of melphalan resistance. The purpose of the ethanol is the protection of RBC catalase activity.

Investigational Treatment Description:

  • Hematopoietic Stem Cell Collection

    1. Granulocyte colony-stimulating factor, and if needed Plerixafor, will be used to mobilize bone marrow stem cells, which will be collected by apheresis.
    2. At least 2 bags of CD34+ cells, each containing at least 2 × 10^6 cells/kg, will be prepared and stored.
    3. Mobilization of hematopoietic stem cells will only occur prior to the first cycle of investigational therapy.
    4. If there is not a sufficient mobilization of stem cells for at least 2 cycles of chemotherapy, then no investigational drugs will be given.
  • Investigational Drug Therapy and Stem Cell Infusion

    1. All subjects will receive two cycles of investigational drug therapy with stem cell infusion unless precluded by adverse reactions.
    2. Subjects will receive on day -2:

      1. BCNU
      2. Melphalan
      3. Vitamin B12b
      4. Vitamin C
      5. Ethanol
    3. On day 0, at least 2 × 10^6 CD34+ cells/kg will be infused as per the institution's standard procedures.
    4. Subjects will receive supportive care as per the institution's standard procedures before, during, and after the investigational drug therapy and stem cell infusion.
  • Additional Cycles a. Subjects will receive a second cycle of the investigational treatment described immediately above in "Investigational Drug Therapy and Stem Cell Infusion," with an interval of approximately 6 weeks between cycles.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of Melphalan, BCNU, Hydroxocobalamin, Ascorbic Acid, and Autologous Bone Marrow Stem Cell Infusion in Patients With Pancreatic Cancer and an Inherited BRCA1 or BRCA2 Mutation
Actual Study Start Date : January 13, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: Chemotherapy/stem cell treatment Drug: Melphalan
Intravenous melphalan (to be given in conjunction with the other listed drugs).

Drug: BCNU
Intravenous BCNU (to be given in conjunction with the other listed drugs).
Other Name: Carmustine

Drug: Vitamin B12B
Intravenous vitamin B12b (to be given in conjunction with the other listed drugs).
Other Name: Hydroxocobalamin

Drug: Vitamin C
Intravenous vitamin C (to be given in conjunction with the other listed drugs).
Other Name: Ascorbic acid, sodium ascorbate

Drug: Ethanol
Intravenous ethanol (to be given in conjunction with the other listed drugs).

Device: Autologous Hematopoietic Stem Cells
After each cycle of chemotherapy, participants will receive an autologous hematopoietic stem cell infusion.




Primary Outcome Measures :
  1. Rate of Sinusoidal obstruction syndrome [ Time Frame: 30 days after treatment ]
    Sinusoidal obstruction syndrome diagnosis and grading will use the European Society for Blood and Marrow Transplantation's Revised Diagnosis and Severity Criteria for Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease in Adult Patients as published in 2016. Gradings are from mild to very severe (multi-organ dysfunction/multi-organ failure).

  2. Rate of Idiopathic or Non-Infective Pulmonary Toxicity [ Time Frame: 3 months after the last treatment ]
    The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.

  3. Rate of Idiopathic or Non-Infective Pulmonary Toxicity [ Time Frame: 6 months after the last treatment ]
    The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.

  4. Rate of Presumptive Oxalate Nephropathy [ Time Frame: Within 48 hours of vitamin C treatment ]
    Oxalate nephropathy will be presumed if there is acute kidney injury or increased creatinine, grade 3 or higher by the criteria of CTCAE Version 5.0 within 48 h of the administration of vitamin C, in the absence of a clear alternative explanation (an example of an alternative explanation is tumor lysis syndrome).

  5. Rate of Mucositis [ Time Frame: Day 7 after each treatment ]
    Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).

  6. Rate of Mucositis [ Time Frame: Day 14 after each treatment ]
    Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).

  7. Rate of Mucositis [ Time Frame: Day 21 after each treatment ]
    Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).

  8. Rate of Delayed Engraftment of Neutrophils [ Time Frame: Day 21 after each treatment ]
    Neutrophil engraftment is defined as an absolute neutrophil count ≥ 500/microliter for 3 days, with the date of engraftment being the first of those 3 days. Delayed engraftment is engraftment that occurs after 21 days but within 30 days.

  9. Rate of Failed Engraftment of Neutrophils [ Time Frame: Day 30 after each treatment ]
    Neutrophil engraftment is defined as an absolute neutrophil count ≥ 500/microliter for 3 days, with the date of engraftment being the first of those 3 days. Failure to engraft within 30 days will be considered an engraftment failure.

  10. Rate of Delayed Engraftment of Platelets [ Time Frame: Day 30 after each treatment ]
    Platelet engraftment is defined as a platelet count ≥ 20,000/microliter for 3 days, with the date of engraftment being the first of those 3 days. Delayed engraftment is engraftment that occurs after 30 days.

  11. Overall incidence rate of adverse events [ Time Frame: Until 12 months after the second stem cell treatment ]
    Adverse event is defined any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.

  12. Overall incidence rate of serious adverse events [ Time Frame: Until 12 months after the second stem cell treatment ]

    An adverse event is considered serious if, in the view of either the investigator or Sponsor, it results in any of the following outcomes:

    • Death.
    • A life-threatening adverse event.
    • Inpatient hospitalization or prolongation of existing hospitalization.
    • A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.
    • A congenital anomaly or birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

  13. Overall incidence rate of Grade 3-5 adverse events [ Time Frame: Until 12 months after the second stem cell treatment ]
    Grading will be measured using Common Terminology Criteria for Adverse Events version 5.0


Secondary Outcome Measures :
  1. Objective response according to RECIST version 1.1 [ Time Frame: 1 month after the first stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  2. Objective response according to RECIST version 1.1 [ Time Frame: 1 month after the second stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  3. Objective response according to RECIST version 1.1 [ Time Frame: 3 months after the second stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  4. Objective response according to RECIST version 1.1 [ Time Frame: 6 months after the second stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  5. Objective response according to RECIST version 1.1 [ Time Frame: 9 months after the second stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  6. Objective response according to RECIST version 1.1 [ Time Frame: 12 months after the second stem cell treatment ]
    Objective response will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  7. Objective response rate in metastatic lesions [ Time Frame: 1 month after the first stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  8. Objective response rate in metastatic lesions [ Time Frame: 1 month after the second stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  9. Objective response rate in metastatic lesions [ Time Frame: 3 months after the second stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  10. Objective response rate in metastatic lesions [ Time Frame: 6 months after the second stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  11. Objective response rate in metastatic lesions [ Time Frame: 9 months after the second stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  12. Objective response rate in metastatic lesions [ Time Frame: 12 months after the second stem cell treatment ]
    Objective response of metastatic lesions will be evaluated according to RECIST version 1.1 as assessed by the independent core imaging facility, but excluding the primary tumor from the analysis. This endpoint will be evaluated with CT scans with contrast of the abdomen, pelvis, and chest and other sites as clinically indicated at each time point.

  13. Overall Survival [ Time Frame: Until 12 months after the second stem cell treatment ]
    Overall survival will be measured from the time of enrollment until death from any cause and will be measured in the intent-to-treat population. Subjects without a known date of death will be censored on the date the subject was last known to be alive.

  14. Progression-Free Survival [ Time Frame: Until 12 months after the second stem cell treatment ]

    Progression-free survival will be measured as time-to-progression with the starting time being the time of enrollment.

    A subject is also considered to have progressed if one of the following occurs:

    • Progression as determined by a RECIST evaluation.
    • Unequivocal evidence of clinical progression.
    • Marked escalation in cancer-related pain that is assessed by the principal investigator to indicate the need for other systemic chemotherapy.
    • Immediate need for initiation of new anticancer treatment or surgical or radiological intervention for complications due to tumor progression even in the absence of radiological progression.
    • Marked deterioration in Karnofsky score felt by the investigator to indicate clinical progression.
    • A determination that it is in the best interest of the subject to come off the study due to clinical progression.
    • Death from any cause.



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:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Age ≥ 18 years.
  • Expected survival time ≥ 6 months, as determined by the investigator.
  • Life expectancy not severely limited by diseases other than malignancy, as determined by the investigator.
  • Karnofsky score ≥ 60%.
  • Potential subjects must have an inherited BRCA1 or BRCA2 mutation (or both), confirmed by Myriad's BRACAnalysis CDx test, and the mutation must be known to be deleterious or suspected to cause functional impairment.
  • Pathologically confirmed ductal adenocarcinoma.
  • Stage IV (based on AJCC staging guidelines) at the time of enrollment.

    a. Note that potential subjects with stage IV cancer that have had a complete response from prior chemotherapy are still potentially eligible.

  • No chemotherapy within 2 weeks of enrollment.
  • If a potential subject has had surgical resection of the primary tumor, then that potential subject must be at least 28 days post-op with the surgical wounds healed and significant complications resolved.
  • Prior surgical resection of the primary tumor is allowed but not required.
  • If the potential subject has had surgical resection of the primary tumor, then there must be no evidence of disease progression between the time of surgical resection of the primary tumor and screening for enrollment if the patient is seeking enrollment in the immediate post-surgery period.
  • Potential subjects who have received previous chemotherapy and/or PARP inhibitors for advanced disease may be enrolled.
  • Histological or cytological confirmation of the primary cancer diagnosis is required.
  • Metastatic disease must be histologically or cytologically confirmed unless in the clinical judgment of the principal investigator a biopsy is not needed for diagnostic purposes.
  • Female participants of childbearing potential must agree to do one of the following from the time of signing of the informed consent through 6 months after the last dose of melphalan:

    1. Simultaneously practice two effective barrier methods of contraception. Oral and injectable contraceptives are not allowed. Barrier methods of birth control (e.g., diaphragm and spermicide, or condom and spermicide) are required.
    2. Practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal) are not acceptable methods of contraception.
  • Male participants:

    1. Unless the male is in a monogamous relationship with a female that does not have child-bearing potential, male subjects (even if surgically sterilized) must agree to do one of the following from the time of signing of the informed consent through 6 months after the last dose of melphalan:

      1. Practice effective barrier contraception, plus a second method of effective contraception.
      2. Practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, and withdrawal) are not acceptable methods of contraception.

Exclusion Criteria

  • Biliary tract obstruction.
  • Prior cholangitis, unless the episode was ≥ 6 months ago. A biliary stent in situ does not otherwise exclude protocol participation.
  • Portal hypertension.
  • Sinistral portal hypertension.
  • Clinically significant malignant ascites or malignant pleural effusion, as determined by the investigator.
  • Metastatic lesion to the heart or eye.
  • Chemotherapy for an indication other than treatment of pancreatic cancer within the past 1 year with a more than 30% risk of recurrence as determined by the investigator.
  • Known or suspected metastatic involvement of the central nervous system.
  • Left ventricular ejection fraction less than 45% by Multigated Acquisition Scan or echocardiogram (or significantly below the lower limit of normal for the specific test).
  • Clinically significant structural heart disease or vascular disease.
  • Myocardial infarction within 6 months prior to enrollment; New York Heart Association (NYHA) Class III or IV heart failure; angina; uncontrolled ventricular arrhythmias; or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
  • Clinically significant prolongation of QTc (Bazett formula) on EKG, defined as > 0.45 s in males and > 0.47 s in females.
  • Severe hypertension, which is defined as the presence of any of the following:

    1. History of hypertensive crisis, hypertensive emergency, or malignant hypertension within the last year.
    2. Sustained or persistent systolic BP > 165 mm Hg or diastolic > 110 mm Hg.
  • Other clinically significant cardiovascular disease.
  • NOTE:

    1. A past history of severe hypertension that is well-controlled with therapy or that was addressed by removal of the cause (e.g., removal of a medicine that caused the severe hypertension) is not an exclusion criterion.
    2. The presence of a pacemaker is not a contraindication and is not considered an exclusion criterion
  • History or evidence of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis).
  • If a smoker, refusal to stop smoking for the duration of the trial.
  • FEV1 or DLCO (adjusted for hemoglobin) < 50% of predicted.
  • Total bilirubin > 2x upper normal limit, except that potential subjects with Gilbert's Disease are permitted to exceed 2x upper normal limit.
  • ALT or AST > 2.5x upper normal limit.
  • Alkaline phosphatase > 2.5x upper normal limit, in conjunction with elevated GGT.
  • Albumin < 3.0 g/dl.
  • Clinical evidence of sinusoidal obstruction syndrome.
  • Corrected creatinine clearance consistently < 50 ml/min/1.73 m^2.
  • Clinically significant renal disease.
  • Hemolytic anemia.
  • Catalase deficiency.
  • Evidence of bone marrow insufficiency or failure, in the judgment of the investigator.
  • A hemoglobin < 9 g/dL.

    a. Note that a hemoglobin < 10 g/dL is not an exclusion criterion provided that the value was subsequently stably increased to ≥ 10 g/dL by the transfusion of RBCs (i.e., there is not active bleeding or hemolysis).

  • G6PD deficiency as measured by quantitative enzyme levels below the normal reference range in blood.
  • Pre-existing bleeding diathesis or coagulopathy.
  • Potential subject is pregnant.
  • Breast feeding and unwilling to stop.
  • Wilson's disease.
  • Primary or secondary hemochromatosis.
  • Hgb A1c > 9%.
  • Hyperuricemia that is not responsive to therapy.
  • Plasma oxalate greater than 10 µM, which is not responsive to measures to reduce the level below 10 µM.

    a. Subjects must be off vitamin C for at least 48 hours prior to the oxalic acid measurements and have fasted overnight.

  • Prior or current hepatitis B or C.
  • HIV infection or seropositivity for HIV.
  • Active, clinically significant bacterial, viral, or fungal infection.
  • History of colonization with a multidrug-resistant "superbug" that poses a high risk of an untreatable infection in the setting of neutropenia.
  • Uncontrolled seizure disorder.
  • If a potential subject has received radiation, then any of the following:

    1. A volume ≥ 700 ml of normal liver received a dose ≥ 4 Gy.
    2. The mean dose to normal liver (i.e., liver minus gross tumor volume) was ≥ 4 Gy.
    3. The mean dose to normal lung (i.e., lung minus gross tumor volume) was ≥ 4 Gy.
  • History of significant allergy or other contraindication to BCNU, melphalan, vitamin B12b, vitamin C, pegfilgrastim, or Neupogen, or to any excipient in those drugs.
  • Use of any of the following cytochrome P450 2b6 (CYP2b6) inducers within 21 days of the planned date of BCNU treatment: phenobarbital, carbamazepam, rifampicin, phenytoin, sulfinpyrazone, or verapamil.
  • Disulfiram (Antabuse) use within 30 days of the planned ethanol administration.
  • Current chronic use of immunosuppressive agents (e.g., methotrexate, cyclosporine, corticosteroids).
  • Prior bone marrow stem cell transplant.
  • Except for adjuvant therapy for breast cancer or pancreatic cancer, prior radiation therapy to the brain, kidneys, pelvis, or GI tract or treatment with yttrium-90.
  • Prior treatment with bleomycin or BCNU.
  • Subject has not fully recovered (i.e., there remain toxicities > Grade 1) from the reversible effects of prior chemotherapy, with the exception of chemotherapy-induced alopecia and grade 2 peripheral neuropathy, unless in the opinion of the principal investigator the effects are not of clinical significance.
  • Any concurrent anticancer treatment.
  • Serious underlying medical or psychiatric illness or another condition that in the clinical judgment of the principal investigator is likely to interfere with the potential subject completing participation in the trial, based on safety concerns or otherwise.
  • Inability or unwillingness to adhere to the study protocol.
  • Unwillingness to receive ethanol, which is used as a co-solvent for BCNU (and which also serves the purpose of protecting RBC catalase in the trial).
  • Participation in other interventional clinical trials within 30 days of enrollment.

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): NCT04150042


Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Colin D Weekes, M.D., Ph.D.    617-724-4000    cdweekes@mgh.harvard.edu   
Principal Investigator: Colin D Weekes, M.D., Ph.D.         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Kenneth H Yu, M.D.    646-888-4188    yuk1@mskcc.org   
Principal Investigator: Kenneth H Yu, M.D.         
Sponsors and Collaborators
General Oncology, Inc.
Investigators
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Principal Investigator: Kenneth H Yu, M.D. Memorial Sloan Kettering Cancer Center
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Responsible Party: General Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04150042    
Other Study ID Numbers: GO-1
First Posted: November 4, 2019    Key Record Dates
Last Update Posted: March 29, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by General Oncology, Inc.:
pancreatic adenocarcinoma
pancreatic cancer
BRCA
BRCA1
BRCA2
melphalan
BCNU
carmustine
vitamin C
vitamin B12b
autologous stem cell infusion
oligometastatic pancreatic cancer
stage 4 pancreatic cancer
metastatic pancreatic cancer
Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Vitamins
Ascorbic Acid
Vitamin B 12
Hydroxocobalamin
Ethanol
Melphalan
Carmustine
Micronutrients
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Antioxidants
Protective Agents