Clinical Trials /

Intravenous Melphalan, BCNU, Vitamin B12b, Vitamin C, Ethanol, and Stem Cell Infusion in Pancreatic Cancer With an Inherited BRCA Mutation

NCT04150042

Description:

The study is a phase 2A, single-arm trial that will evaluate the effectiveness and safety of the investigational treatment on oligometastatic pancreatic cancer following resection of the primary tumor in patients who have an inherited, deleterious BRCA1 or BRCA2 genetic alteration. The investigational treatment will involve 2 (and possibly 3) cycles of a combination of intravenous: melphalan, BCNU, low-dose ethanol, vitamin B12b, and vitamin C in association with autologous hematopoietic stem cell infusion. A dose-escalation schedule will be employed for vitamin C.

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intravenous Melphalan, BCNU, Vitamin B12b, Vitamin C, Ethanol, and Stem Cell Infusion in Pancreatic Cancer With an Inherited BRCA Mutation
  • Official Title: A Phase 2A Trial of Melphalan, BCNU, Hydroxocobalamin, Ascorbic Acid, and Autologous Bone Marrow Stem Cell Infusion in Patients With Oligometastatic Pancreatic Cancer Post-Surgery and an Inherited BRCA1 or BRCA2 Mutation

Clinical Trial IDs

  • ORG STUDY ID: GO-1
  • NCT ID: NCT04150042

Conditions

  • Pancreatic Adenocarcinoma Metastatic
  • BRCA1 Mutation
  • BRCA2 Mutation

Interventions

DrugSynonymsArms
MelphalanChemotherapy/stem cell treatment
BCNUCarmustineChemotherapy/stem cell treatment
Vitamin B12BHydroxocobalaminChemotherapy/stem cell treatment
Vitamin CAscorbic acid, sodium ascorbateChemotherapy/stem cell treatment
EthanolChemotherapy/stem cell treatment

Purpose

The study is a phase 2A, single-arm trial that will evaluate the effectiveness and safety of the investigational treatment on oligometastatic pancreatic cancer following resection of the primary tumor in patients who have an inherited, deleterious BRCA1 or BRCA2 genetic alteration. The investigational treatment will involve 2 (and possibly 3) cycles of a combination of intravenous: melphalan, BCNU, low-dose ethanol, vitamin B12b, and vitamin C in association with autologous hematopoietic stem cell infusion. A dose-escalation schedule will be employed for vitamin C.

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 and Enrichment:

             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. The CliniMACS CD34 Reagent System will be used to enrich CD34+ cells. 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 at least two cycles of investigational drug therapy with
                stem cell infusion unless precluded by adverse reactions.

             2. Subjects will receive on day −2:

                  1. I.V. melphalan

                  2. I.V. BCNU

                  3. I.V. Vitamin B12b

                  4. I.V. Vitamin C (a dose-escalation schedule will be employed)

                  5. Ethanol (as cosolvent with the BCNU infusion, followed by a low dose infusion
                     for 23 h).

             1. On day 0, at least 2 × 10^6 CD34+ cells/kg will be infused as per the institution's
                standard procedures.

             2. 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: Subjects will receive a second cycle (with the possibility of a third
           cycle) of the investigational treatment with an interval of approximately 6 weeks
           between cycles.
    

Trial Arms

NameTypeDescriptionInterventions
Chemotherapy/stem cell treatmentExperimental
  • Melphalan
  • BCNU
  • Vitamin B12B
  • Vitamin C
  • Ethanol

Eligibility Criteria

        Inclusion Criteria

          -  18 years ≤ age < 64 years when eligibility pre-screening begins.

          -  Expected survival time ≥ 6 months.

          -  Life expectancy not severely limited by diseases other than malignancy.

          -  Karnofsky score ≥ 60%

          -  Potential subjects must have an inherited BRCA1 and 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.

          -  Measurable metastatic disease by RECIST v1.1 criteria.

          -  Oligometastatic disease with no more than 3 metastatic lesions detected on tumor
             imaging or at laparoscopy, excluding metastases to lymph nodes. (More than 3
             metastatic lesions can be present at diagnosis provided that no more than 3 lesions
             remain after neoadjuvant chemotherapy or other therapy (e.g., surgery)).

          -  Absence of malignant ascites.

          -  No metastatic lesions in bone detected on bone scan or other tumor imaging.

          -  If the subject was treated with neoadjuvant platinum-based therapy, then there must
             be:

               1. Objective evidence of a response with at least one of the following:

                    1. Normalization or a confirmed decrease in an elevated tumor marker of greater
                       than 50%.

                    2. A partial or complete response by RECIST criteria. Confirmation by a repeat
                       scan is not required.

                    3. Pathological evidence of a response (Evans Grade III or IV or College of
                       American Pathologists Grade 0 or 1).

               2. 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.

          -  The primary tumor and surgically resectable bulk tumor must have been surgically
             removed.

          -  Subject must be greater than 28 days after major surgery (e.g., Whipple) or
             tumor-ablation procedures, with the surgical wounds healed and significant
             complications resolved.

          -  Independent histological confirmation of the primary cancer diagnosis is required.

          -  Metastatic disease must be histologically or cytologically confirmed.

          -  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:

             a. 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.

          -  Informed Consent

               1. Competency to comprehend, sign, and date informed consent forms.

               2. Signature of an IRB-approved informed consent for enrollment.

               3. Agreement and ability to comply with the study visit schedule and other protocol
                  requirements.

               4. Agreement to provide copies of complete medical records.

        Exclusion Criteria

          -  A measurable tumor burden exceeding 20 ml (with a margin of error of +25% or +5 ml) as
             assessed by the independent core imaging facility.

          -  The presence of extensive metastatic spread (e.g., miliary lung disease with a large
             number of 1-4 mm lung metastatic lesions).

          -  Malignant ascites or malignant pleural effusion.

          -  Metastatic lesion to the heart or eye.

          -  Chemotherapy for an indication other than neoadjuvant treatment of pancreatic cancer
             within the past 5 years.

          -  Advanced or rapidly progressive disease with an expected survival of less than 6
             months.

          -  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.

          -  History of long QT syndrome.

          -  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.

          -  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) < 70% 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.

          -  Albumin < 2.7 g/dl.

          -  Corrected creatinine clearance consistently ≤ 55 ml/min/1.73 m^2.

          -  Clinically significant renal disease.

          -  Hemolytic anemia.

          -  Catalase deficiency.

          -  Evidence of bone marrow insufficiency or failure.

          -  An absolute neutrophil count < 1500/µL.

          -  A platelet count < 100,000/µL.

          -  A hemoglobin < 10 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.

          -  Unwillingness to receive blood products if needed.

          -  Pre-existing bleeding diathesis or coagulopathy.

          -  Pulmonary embolism, deep vein thrombosis, or other significant thromboembolic event
             that requires continued anticoagulation.

          -  Potential participant is pregnant.

          -  Breast feeding and unwillingness to stop.

          -  Wilson's disease.

          -  Primary or secondary hemochromatosis.

          -  Hgb A1c > 9%.

          -  Hyperuricemia that is not responsive to therapy.

          -  Hyperoxalemia with plasma oxalate greater than 10 µM, which is not responsive to
             measures to reduce the level below 10 µM.

          -  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, iron-dextran, mouse
             proteins, 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.

          -  Prior radiation therapy to the brain, kidneys, pelvis, or GI tract.

          -  Prior treatment with any of the following drugs: bleomycin, BCNU, a PARP inhibitor,
             oxaliplatin, gemcitabine, cisplatin, and carboplatin; except that:

             a. Neoadjuvant treatment with cisplatin or carboplatin, with or without gemcitabine is
             allowed.

               1. The cumulative maximum permitted dose of neoadjuvant cisplatin is 450 mg/m^2.

               2. The cumulative maximum permitted dose of neoadjuvant carboplatin is an AUC of 24
                  mg min/ml (e.g., 4 cycles, each with an AUC ≤ 6 mg min/ml).

          -  Prior treatment with yttrium-90.

          -  Clinical evidence of tumor resistance to DNA-crosslinking agents, including
             platinum-based drugs, cyclophosphamide, melphalan, or ifosfamide.

          -  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.
      
Maximum Eligible Age:64 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of the treatment protocol evaluated according to CTCAE Version 5.0
Time Frame:From enrollment to 60 months since the last stem cell infusion
Safety Issue:
Description:Safety of the treatment protocol will be evaluated according to CTCAE Version 5.0. Pretreatment histories, physical exams, and clinical and laboratory studies will serve as a baseline. All adverse reactions will be recorded, as well as the clinical setting in which the reactions occurred. Overall incidence rates for: Adverse events, serious adverse events, Grade 3-5 adverse events, by the criteria of CTCAE Version 5.0.

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:Up to 60 months after the last stem cell infusion
Safety Issue:
Description: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.
Measure:Physical Well-Being as Measured by Functional Assessment of Cancer Therapy: General (FACT-G) Version 4
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 0 to 28, with higher scores signifying a worse outcome.
Measure:Social/Family Well-Being as Measured by Functional Assessment of Cancer Therapy: General (FACT-G) Version 4
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 0 to 28, with higher scores signifying a better outcome.
Measure:Emotional Well-Being as Measured by Functional Assessment of Cancer Therapy: General (FACT-G) Version 4
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 0 to 24, with higher scores signifying a worse outcome.
Measure:Functional Well-Being as Measured by Functional Assessment of Cancer Therapy: General (FACT-G) Version 4
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 0 to 28, with higher scores signifying a better outcome.
Measure:Pancreatic Cancer Symptoms as Measured by National Comprehensive Cancer Network Functional Assessment of Cancer Therapy - Hepatobiliary-Pancreatic Symptom Index (NCCN-FACT FHSI-18) Version 2
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 0 to 72, with higher scores signifying a worse outcome.
Measure:Pain Interference as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 - Pain Interference - Short Form 8a
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 8 to 40, with higher scores signifying a worse outcome.
Measure:Pain Intensity as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 - Pain Intensity - Short Form 3a
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 3 to 15, with higher scores signifying a worse outcome.
Measure:Physical Function as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Ca Bank v1.1 - Physical Function
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:Scores range from 45 to 225, with higher scores signifying a better outcome.
Measure:Patient-Reported Outcomes as Measured by National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library Version 1.0
Time Frame:Monthly through the last chemotherapy treatment, as well as monthly for 3 months after the last chemotherapy treatment, then every 3 months for 9 months, then every 6 months for 4 years
Safety Issue:
Description:PRO-CTCAE responses are scored from 0 to 4. There are no standardized scoring rules on how to combine the attributes into a single score or on how best to analyse PRO-CTCAE data longitudinally. PRO-CTCAE scores for each attribute (frequency, severity and/or interference) will be presented descriptively.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:General Oncology, Inc.

Trial Keywords

  • 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

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