SHARON: Study of Metastatic Cancers in Patients Using Autologous Stems Cells and Potentiated Redox Cycling to Overcome Drug Resistance to Nitrogen Mustard Derivatives
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- General Oncology, Inc.
- Enrollment
- 24
- Locations
- 2
- Primary Endpoint
- Overall incidence rate of adverse events
Study 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
- Granulocyte colony-stimulating factor, and if needed Plerixafor, will be used to mobilize bone marrow stem cells, which will be collected by apheresis.
- At least 2 bags of CD34+ cells, each containing at least 2 × 10^6 cells/kg, will be prepared and stored.
- Mobilization of hematopoietic stem cells will only occur prior to the first cycle of investigational therapy.
- 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
- All subjects will receive two cycles of investigational drug therapy with stem cell infusion unless precluded by adverse reactions.
- Subjects will receive on day -2:
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
- •Potential subjects who have received previous chemotherapy and/or PARP inhibitors may be enrolled.
- •Measurable or non-measurable disease by the revised response evaluation criteria in solid tumors (RECIST) v.1.
- •For potential subjects with a germline BRCA1, BRCA2, or PALB2 mutation:
- •a. The mutation must be known to be deleterious or suspected to cause functional impairment as assessed by a CLIA-certified laboratory according to the variant classification criteria described in the study protocol.
- •For potential subjects with somatic BRCA1, BRCA2, or PALB2 mutations:
- •The mutation must be a known or suspected deleterious mutation as assessed by a CLIA-certified laboratory according to the variant classification criteria described in the study protocol.
- •There must be biallelic loss or inactivation of the mutated BRCA1, BRCA2, or PALB2 gene as assessed by a CLIA-certified laboratory.
- •The Genetics Review Committee for this trial, which is comprised of a core group of investigators and whose actions are performed in accordance with the committee's charter, must agree that the biallelic mutations are deleterious or suspected deleterious.
- •For subjects without a BRCA1, BRCA2, or PALB2 mutation
- •Subject must have received at least 16 weeks of first-line (platinum-based*) chemotherapy with no evidence of treatment failure, where treatment failure is defined as growing tumors, new lesions, or a steadily rising tumor marker during or within eight weeks of completion of the first line therapy.
- •* Subjects can also have been treated with FOLFIRINOX but switched to FOLFIRI due to oxaliplatin side effects.
- •For potential subjects with pancreatic cancer:
- •Pancreatic ductal adenocarcinoma or pancreatic acinar cell carcinoma.
- •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.
- •For potential subjects with breast cancer:
- •Adenocarcinoma of the breast.
- •HER2-negative cancer as per American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guidelines.
- •Male or female sex.
- •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 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:
- •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.
- •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:
- •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:
- •Practice effective barrier contraception, plus a second method of effective contraception.
- •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
- •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.
- •Chemotherapy for an indication other than treatment of the current 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:
- •History of hypertensive crisis, hypertensive emergency, or malignant hypertension within the last year.
- •Sustained or persistent systolic BP > 165 mm Hg or diastolic > 110 mm Hg.
- •Other clinically significant cardiovascular disease.
- •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.
- •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^
- •Clinically significant renal disease.
- •Hemolytic anemia.
- •Family history of catalase deficiency or history or evidence of a severe adverse reaction to hydrogen peroxide consistent with catalase deficiency, unless testing has demonstrated that the patient is not catalase-deficient.
- •Evidence of bone marrow insufficiency or failure, in the judgment of the investigator.
- •A hemoglobin < 9 g/dL.
- •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.
- •History of clinically significant elevation of plasma oxalic acid or complications related to oxalic acid.
- •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.
- +18 more not shown
Arms & Interventions
Chemotherapy/stem cell treatment
Intervention: Vitamin B12B (Drug)
Chemotherapy/stem cell treatment
Intervention: Vitamin C (Drug)
Chemotherapy/stem cell treatment
Intervention: Melphalan (Drug)
Chemotherapy/stem cell treatment
Intervention: BCNU (Drug)
Chemotherapy/stem cell treatment
Intervention: Autologous Hematopoietic Stem Cells (Device)
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)