The clinical trial is a phase 1, single-arm trial that will evaluate the safety of the
investigational treatment on pancreatic cancer in patients who have an inherited, deleterious
BRCA1 or BRCA2 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
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
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. Melphalan (100 mg/m^2 I.V.).
2. BCNU (150 mg/m^2 I.V.).
3. Vitamin B12b (1450 mg/m^2 I.V.).
4. Vitamin C (a dose-escalation schedule will be employed beginning with 3 g/m^2
I.V. and escalating to a maximum of 8 g/m^2 I.V.).
5. Ethanol (3.5 g/m^2 I.V. as cosolvent with the BCNU infusion, followed by 0.5
g/h I.V. for 23 h).
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.
Inclusion Criteria
- 18 years ≤ age < 71.
- 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 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.
a. Note that potential subjects with stage IV cancer that have had a complete response
from prior chemotherapy are still potentially eligible.
- Absence of malignant ascites.
- The estimated volume of metastatic tumor burden (not taking into account lymph node
lesions or the primary tumor) based on CT imaging must be ≤ 20 ml (with a margin of
error of +25% or +5 ml) as assessed by the core imaging laboratory.
1. The following steps will be used to calculate the volume of each metastasis
(other than lymph node lesions):
1. Measure the metastasis in 3-D and determine the maximum transverse diameter
(L), perpendicular diameter (W), and craniocaudal height (H).
2. Apply the formula for the volume of an ellipsoid, V = L x W x H x 0.52.
2. The estimated volume of metastatic tumor burden will be the sum of those
estimated volumes.
- Prior treatment with a platinum-based therapy is required with (1) no evidence of
disease progression and (2) objective evidence of a response by at least one of the
following:
1. Normalization or a confirmed decrease in an elevated tumor marker of ≥ 50%.
2. A partial or complete response by RECIST version 1.1 criteria.
3. Pathological evidence of a response (Evans Grade III or IV or College of American
Pathologists Grade 0 or 1).
- Except for subsequent treatment with PARP inhibitors, the platinum-based therapy must
be the last chemotherapy received by the subject.
- No chemotherapy within 3 weeks of enrollment.
- If a potential subject has had surgical resection of the primary tumor, then that
potential subject must be at least 28 days post-op with the surgical wounds healed and
significant complications resolved.
- 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.
- Prior surgical resection of the primary tumor is allowed but not required.
- Independent histological confirmation of the primary cancer diagnosis is required.
- Metastatic disease must be histologically or cytologically confirmed unless in the
clinical judgment of the principal 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:
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.
- Competency to comprehend, sign, and date informed consent forms.
a. A potential subject's legally authorized representative is not allowed to provide
informed consent for this trial.
- Signature of an IRB-approved informed consent for enrollment.
- Agreement and ability to comply with the study visit schedule and other protocol
requirements.
- Agreement to provide copies of complete medical records.
Exclusion Criteria
- Biliary tract obstruction.
- Biliary stenting.
- Portal hypertension.
- Sinistral portal hypertension.
- History of cholangitis related to the pancreatic cancer.
- 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 treatment of pancreatic cancer within the
past 5 years.
- 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.
- NOTE:
1. 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.
2. 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 < 2.7 g/dl.
- Clinical evidence of sinusoidal obstruction syndrome.
- 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 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.
a. Subjects must be off vitamin C for at least 48 hours prior to the oxalic acid
measurements and have fasted overnight.
- 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, 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 or treatment with
yttrium-90.
- Prior treatment with bleomycin or BCNU.
- Clinical evidence of tumor resistance to DNA-crosslinking agents, including
platinum-based drugs, cyclophosphamide, melphalan, or ifosfamide.
- If a PARP inhibitor is the last chemotherapy received, then clinical or radiographical
evidence of tumor resistance to PARP inhibitors.
- 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.
