SHARON: Study of Metastatic Cancers in Patients Using Autologous Stems Cells and Potentiated Redox Cycling to Overcome Drug Resistance to Nitrogen Mustard Derivatives
Overview
- Phase
- Phase 1
- Intervention
- Vitamin B12B
- Conditions
- Pancreatic Adenocarcinoma Metastatic
- Sponsor
- General Oncology, Inc.
- Enrollment
- 24
- Locations
- 2
- Primary Endpoint
- Overall incidence rate of adverse events
- Status
- Recruiting
- Last Updated
- 3 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years.
- •Pancreatic or breast cancer, as described below.
- •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.
- •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%.
- •No chemotherapy within 2 weeks of enrollment.
- •Prior surgical resection or ablation of the primary tumor is allowed but not required.
- •If post-surgical, the subject must be at least 28 days post-op with the surgical wounds healed and significant complications resolved.
Exclusion Criteria
- •Rapid disease progression or clinical features concerning for onset of rapid symptomatic deterioration, as determined by the investigator.
- •Biliary tract obstruction.
- •Current cholangitis. A biliary stent in situ does not otherwise exclude protocol participation.
- •A history of only one episode of cholangitis and fewer than 30 days have passed since discontinuation of antibiotic treatment.
- •A history of multiple episodes of cholangitis and after discussion between the site study team and sponsor medical monitor and careful evaluation for suitability the patient is deemed to be unsuitable for the trial due to risk of recurring cholangitis.
- •Portal hypertension.
- •Sinistral portal hypertension.
- •Obliteration or significant obstruction of the major veins or arteries (e.g., portal vein, superior mesenteric artery, superior mesenteric vein).
- •Clinically significant malignant ascites or malignant pleural effusion, as determined by the investigator.
- •Metastatic lesion to the heart or eye.
Arms & Interventions
Chemotherapy/stem cell treatment
Intervention: Vitamin B12B
Chemotherapy/stem cell treatment
Intervention: Vitamin C
Chemotherapy/stem cell treatment
Intervention: Melphalan
Chemotherapy/stem cell treatment
Intervention: BCNU
Chemotherapy/stem cell treatment
Intervention: Autologous Hematopoietic Stem Cells
Outcomes
Primary Outcomes
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.
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.
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).
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
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).
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.
Rate of Mucositis ≥ Grade 3
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).
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.
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.
Rate of Idiopathic or Non-Infective Pulmonary Toxicity ≥ Grade 3
Time Frame: 3 months after the last treatment
The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.
Rate of Idiopathic or Non-Infective Pulmonary Toxicity ≥ Grade 3
Time Frame: 6 months after the last treatment
The American Thoracic Society Committee on Idiopathic Pneumonia Syndrome definition will be employed.
Rate of Cytokine Release Syndrome ≥ Grade 3
Time Frame: Within 48 hours of each vitamin C treatment
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.
Rate of Mucositis ≥ Grade 3
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).
Rate of Mucositis ≥ Grade 3
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).
Secondary Outcomes
- Overall Survival(Until 12 months after the second stem cell treatment)
- Progression-Free Survival(Until 12 months after the second stem cell treatment)
- Objective response according to RECIST version 1.1(12 months after the second stem cell treatment)
- Objective response rate in metastatic lesions(12 months after the second stem cell treatment)
- Objective response according to RECIST version 1.1(1 month after the first stem cell treatment)
- Objective response according to RECIST version 1.1(1 month after the second stem cell treatment)
- Objective response according to RECIST version 1.1(3 months after the second stem cell treatment)
- Objective response according to RECIST version 1.1(6 months after the second stem cell treatment)
- Objective response according to RECIST version 1.1(9 months after the second stem cell treatment)
- Objective response rate in metastatic lesions(1 month after the first stem cell treatment)
- Objective response rate in metastatic lesions(1 month after the second stem cell treatment)
- Objective response rate in metastatic lesions(3 months after the second stem cell treatment)
- Objective response rate in metastatic lesions(6 months after the second stem cell treatment)
- Objective response rate in metastatic lesions(9 months after the second stem cell treatment)