A Phase Ib Study to Evaluate Safety and Persistence of ex Vivo Expanded Universal Donor NK Cells in Combination With IL-2 and TGFbeta Receptor I Inhibitor Vactosertib in Patients With Locally Advanced/Metastatic Colorectal Cancer and Relapsed/Refractory Hematologic Malignancies NK CELLS PLUS VACTOSERTIB

What's the purpose of this trial?

The purpose of this study is to show that using two medicines (vactosertib and IL-2) with NK cells will be safe and will activate the donor NK cells. 

This trial is currently open and accepting patients.

What will happen during the trial?

The objective of this research is to demonstrate that natural killer (NK) cells from non-Human Leukocyte Antigen (HLA)-matched donors can be safely infused into colorectal cancer patients and patients with relapsed/refractory hematologic malignancies in combination with IL-2 and the oral transforming growth factor beta (TGFβ) receptor I inhibitor vactosertib to improve the persistence of donor NK cells.

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

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

Additional Trial Information

Phase 1

Enrollment: 12 patients (estimated)

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Case Comprehensive Cancer Center Case Western Reserve University

Cleveland, OH

Open and Accepting
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