| Eligibility |
Inclusion Criteria:
- Subjects must have histologically confirmed locally advanced or metastatic colorectal
adenocarcinoma or relapsed or refractory hematologic malignancy and have failed at
least one standard line of chemotherapy. Participants will be eligible if they have
either refused standard treatment regimens or if there is no standard approach to
curative salvage therapy per National Comprehensive Cancer Network (NCCN) guidelines
in the setting of relapsed/refractory disease.
Malignancies can include:
- Acute myeloid leukemia
- Myelodysplastic syndrome
- Acute lymphoblastic leukemia
- Chronic myeloid leukemia
- Chronic lymphocytic leukemia
- Non Hodgkin Lymphoma
- Hodgkin Lymphoma
- Myeloproliferative syndromes
- Plasma cell myeloma
- Colon and/or rectal adenocarcinoma
- Subjects must have recovered from acute toxicities of prior chemotherapy or stem
cell transplant. Any prior non-hematologic vital organ toxicity (cardiac,
pulmonary, hepatic, renal) of previous therapy must have resolved to grade 1 or
less. Exceptions: Alopecia; subjects with chemotherapy-induced sensory neuropathy
must have grade = 3
- Age =18 years. Because no dosing or adverse event data are currently available on
the use of NK cells in subjects =18 years of age, children are excluded from this
study.
- Eastern Cooperative Oncology Group (ECOG) Performance status =2
- Subjects must have normal organ and marrow function as defined below:
- Serum total bilirubin <2 mg/dl. If known Gilbert syndrome, total bilirubin
must be <3mg/dl
- Aspartate aminotransferase (AST) < 2.5 X institutional upper limit of normal
- Alanine Aminotransferase (ALT) < 2.5 X institutional upper limit of normal
- Pulmonary function (DLCO) >40% of the expected value corrected for alveolar
volume and hemoglobin
- Serum Creatinine = 1.5 X institutional upper limit of normal
- Hemoglobin = 7.5 g/dL
- Absolute neutrophil count = 1,250/mcL for colorectal cancer (CRC) patients
or = 1,000/mcL for patients with hematologic malignancies unless patient has
bone marrow involvement of hematological malignancy
- Platelet count = 50,000/mcL
- Women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) 4 weeks prior to study
entry and for the duration of study participation. Women of child-bearing age
must have documented negative pregnancy test prior to start of lymphodepleting
regimen.
- Subjects must have the ability to understand and the willingness to sign a
written informed consent document.
- Subjects must have at least 3 weeks between last cytotoxic anti-neoplastic
medication and initiation of preparative regimen.
Exclusion Criteria:
- Subjects receiving any other investigational agents
- Subjects requiring systemic corticosteroid therapy (10mg or less of prednisone or
equivalent doses of other systemic steroids are permitted).
- Subjects for whom a potential 29-day delay in treatment will interfere with their
potential therapeutic options
- Patients with active, untreated malignant involvement of the central nervous system
(CNS) should be excluded from this clinical trial because of their poor prognosis and
because they often develop progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events. If clinical suspicion for CNS
involvement head imaging will be necessary to document absence of active CNS
involvement in patients with colon/rectal cancer. Patients with hematologic
malignancies who have undergone treatment for malignant involvement of the CNS must
have no evidence of residual disease by imaging or cerebrospinal fluid (CSF) sampling
prior to study enrollment.
- History of allergic reactions to fludarabine or cyclophosphamide
- Subjects with uncontrolled intercurrent illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.
- Pregnant or breastfeeding women are excluded from this study because cytotoxic agents
used as part of the lymphodepleting regimen have the potential for teratogenic or
abortifacient effects. Because there is an unknown, but potential risk for adverse
events in nursing infants secondary to treatment of the mother with lymphodepleting
chemotherapy, breastfeeding should be discontinued if the mother participates in the
trial. These potential risks may also apply to other agents used in this study.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with chemotherapeutic agents. In
addition, these patients are at increased risk of lethal infections when treated with
marrow suppressive therapy.
- Chronic active untreated hepatitis B or C infection. (Assessments should include
Hepatitis B Surface Ab, Hepatitis B Surface Ag, Hepatitis B Core Ab - Total, Hepatitis
B Core Ab, IGM, Hepatitis C Ab).
- Recipients of previous allogeneic transplants who have rash involving more than 10%
body surface area attributed to graft versus host disease (GVHD). Stem cell transplant
recipients will be excluded if they are still receiving immunosuppression including
steroids for GVHD or have active GVHD in any organ (except for 10% BSA of skin, not
requiring treatment).
- Subject who is taking prohibited medications when using vactosertib as following
(refer to APPENDIX III). A minimal washout period of 5 half-lives for the following
drugs is recommended prior to the first dosing.
- Concurrent use of drugs or foods that are known strong CYP3A4 inhibitors
including but not limited to grapefruit juice, itraconazole, ketoconazole,
lopinavir/ritonavir, mibefradil, voriconazole. The topical use of these
medications (if applicable), such as 2% ketoconazole cream, may be allowed.
- Concurrent use of drugs that are known potent CYP3A4 inducers including but not
limited to phenytoin, rifampin, St. John's wort.
- Concurrent use of drugs that are CYP3A4, CYP1A2, CYP2B6 substrates with narrow
therapeutic indices including but not limited to theophylline, astemizole,
cisapride, cyclosporine, dihydroergotamine, ergotamine, sirolimus, tacrolimus,
terfenadine (astemizole, cisapride, and terfenadine have been withdrawn from the
US market).
- Concurrent use of drugs that are sensitive CYP3A4, CYP1A2, CYP2B6 substrates
including but not limited to efavirenz, darunavir, dasatinib, everolimus,
lopinavir, midazolam, sirolimus, ticagrelor.
- QT interval corrected for heart rate using Fridericia's formula (QTcF) =470 ms
calculated from 12-lead ECGs
|
