The clinical trial is a phase 1, single-arm trial that will evaluate the safety of the investigational treatment on metastatic pancreatic cancer and metastatic breast cancer. The investigational treatment will involve 2 cycles of a combination of intravenous melphalan, BCNU, vitamin B12b, and vitamin C with autologous hematopoietic stem cell infusion. A dose-escalation schedule is being employed for the vitamin C.
In the current clinical trial, subjects will receive a combination of melphalan, BCNU, vitamin B12b, and vitamin C in conjunction with autologous stem cell infusion. The drug combination is designed to address multiple mechanisms of melphalan resistance. 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 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Intravenous melphalan (to be given in conjunction with the other listed drugs).
Intravenous BCNU (to be given in conjunction with the other listed drugs).
Intravenous vitamin B12b (to be given in conjunction with the other listed drugs).
Intravenous vitamin C (to be given in conjunction with the other listed drugs).
After each cycle of chemotherapy, participants will receive an autologous hematopoietic stem cell infusion.
Massachusetts General Hospital
Boston, Massachusetts, United States
COMPLETEDMemorial Sloan Kettering Cancer Center
New York, New York, United States
RECRUITINGRate of Sinusoidal obstruction syndrome
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).
Time frame: 30 days after treatment
Rate of Idiopathic or Non-Infective Pulmonary Toxicity ≥ Grade 3
The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.
Time frame: 3 months after the last treatment
Rate of Idiopathic or Non-Infective Pulmonary Toxicity ≥ Grade 3
The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.
Time frame: 6 months after the last treatment
Rate of Presumptive Oxalate Nephropathy
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).
Time frame: Within 48 hours of vitamin C treatment
Rate of Cytokine Release Syndrome ≥ Grade 3
Cytokine release syndrome will be assessed by the criteria of CTCAE Version 5.0. Elevation of plasma cytokine levels consistent with the diagnosis of cytokine release syndrome must be present.
Time frame: Within 48 hours of each vitamin C treatment
Rate of Mucositis ≥ Grade 3
Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).
Time frame: Day 7 after each treatment
Rate of Mucositis ≥ Grade 3
Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).
Time frame: Day 14 after each treatment
Rate of Mucositis ≥ Grade 3
Mucositis will be assessed using the WHO Mucositis Scale. Grading is from 0 (no symptoms) to 4 (no possible alimentation).
Time frame: Day 21 after each treatment
Rate of Delayed Engraftment of Neutrophils
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.
Time frame: Day 21 after each treatment
Rate of Failed Engraftment of Neutrophils
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.
Time frame: Day 30 after each treatment
Rate of Delayed Engraftment of Platelets
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.
Time frame: Day 30 after each treatment
Overall incidence rate of adverse events
Adverse event is defined any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.
Time frame: Until 12 months after the second stem cell treatment
Overall incidence rate of serious adverse events
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.
Time frame: Until 12 months after the second stem cell treatment
Overall incidence rate of Grade 3-5 adverse events
Grading will be measured using Common Terminology Criteria for Adverse Events version 5.0
Time frame: Until 12 months after the second stem cell treatment
Objective response according to RECIST version 1.1
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.
Time frame: 1 month after the first stem cell treatment
Objective response according to RECIST version 1.1
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.
Time frame: 1 month after the second stem cell treatment
Objective response according to RECIST version 1.1
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.
Time frame: 3 months after the second stem cell treatment
Objective response according to RECIST version 1.1
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.
Time frame: 6 months after the second stem cell treatment
Objective response according to RECIST version 1.1
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.
Time frame: 9 months after the second stem cell treatment
Objective response according to RECIST version 1.1
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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.
Time frame: 12 months after the second stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 1 month after the first stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 1 month after the second stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 3 months after the second stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 6 months after the second stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 9 months after the second stem cell treatment
Objective response rate in metastatic lesions
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.
Time frame: 12 months after the second stem cell treatment
Overall Survival
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.
Time frame: Until 12 months after the second stem cell treatment
Progression-Free Survival
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.
Time frame: Until 12 months after the second stem cell treatment