SHARON: Study of Metastatic Cancers in Patients With a Defect in a Homologous Recombination Gene Using Autologous Stems Cells and Potentiated Redox Cycling to Overcome Drug Resistance to Nitrogen Mustard Derivatives
The clinical trial is a phase 1, single-arm trial that will evaluate the safety of the investigational treatment on metastatic cancer in patients who have a deleterious or suspected deleterious BRCA1, BRCA2, or PALB2 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.
• 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.1.1.
• A germline or somatic BRCA1, BRCA2, or PALB2 mutation.
• For potential subjects with a germline 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 mutations:
‣ The mutation must be a known or suspected deleterious somatic BRCA1, BRCA2, or PALB2 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 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.