Multiple Myeloma, NHL, Non-Hodgkins Lymphoma, Pancreatic Neuroendocrine Tumors, PNET, Solid Tumors
Conditions
Brief summary
The purpose of this study is to assess the safety and tolerability of the investigational anticancer drug DCR-MYC. DCR-MYC is a novel synthetic double-stranded RNA in a stable lipid particle suspension that targets the oncogene MYC. MYC oncogene activation is important to the growth of many hematologic and solid tumor malignancies. In this study the Sponsor proposes to study DCR-MYC and its ability to inhibit MYC and thereby inhibit cancer cell growth.
Detailed description
In this first-in human study, DCR-MYC will be administered by 2 hour intravenous (IV) infusion, once weekly for 2 weeks followed by a rest week (3 weeks = 1 cycle), to patients with either solid tumor malignancies, multiple myeloma, or non-Hodgkins lymphoma that have not responded to previous treatment. The highest safe dose of DCR-MYC that can be administered will be identified. In addition, the pharmacokinetic (PK) profile, potential pharmacodynamic (PD) effects, as well as the antitumor activity of DCR-MYC will be evaluated. There will be 2 expansion cohorts at the maximum tolerated dose (MTD) (or highest safe dose identified for further study which may be lower): * Biopsy Cohort: 6 patients, tumor biopsies to be performed pre-dosing and Cycle 2/Day 11; same assessments as dose escalation cohorts * PNET Cohort: Up to 20 patients with pancreatic neuroendocrine tumors; same assessments as dose escalation cohorts, however fewer PD (cytokine) assessments and no PK assessments
Interventions
DRUGDCR-MYC
Dosing: 2 hour IV infusion on Day 1 and 8 of each 21 day cycle. Starting dose: 0.1mg/kg/dose Dose escalation: 100%, 50%, or 25% increase in subsequent cohorts depending upon toxicity. Number of cycles: until progression or unacceptable toxicity develops.
Sponsors
Dicerna Pharmaceuticals, Inc., a Novo Nordisk company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients, \> 18 years of age at the time of obtaining informed consent. 2. Patients with a documented solid tumor malignancy that is locally advanced or metastatic; patients with documented multiple myeloma or non-Hodgkin's lymphoma. 3. Patients with a malignancy that is either refractory to standard therapy or for which no standard therapy is available. 4. Patients with a malignancy that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor. 5. Dose escalation portion of study: Patients with measurable or non-measurable disease according to standard response criteria . 6. MTD Biopsy Cohort ONLY: Patients with measurable disease with primary or metastatic tumor site(s) considered safely accessible for biopsy; patients must consent to undergo 2 tumor biopsies. 7. MTD PNET Cohort ONLY: Patients with advanced (unresectable or metastatic), histologically-confirmed low or intermediate grade PNET according to the World Health Organization (WHO) 2010 classification. Patients with neuroendocrine tumors (e.g., gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary is strongly suspected are also eligible. Patients must also have: * A Ki-67 proliferation index \< 20% * Demonstrated radiological evidence of disease progression during or following the last treatment regimen (based on CT, MRI, or Octreoscan®) * Measurable disease according to RECIST v1.1 (determined by CT or MRI). Any lesions which have been subjected to percutaneous therapies or radiotherapy should not be considered measureable, unless the lesion has clearly progressed (per RECIST v1.1) since the procedure. * Received \< 2 prior systemic treatments for PNET, at least one of which must have been an FDA-approved targeted therapy for PNET (i.e., sunitinib \[Sutent®\] or everolimus \[Afinitor®\]). Treatment with a somatostatin analog (SSA) will not be considered as a systemic treatment for the purposes of eligibility. 8. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and an anticipated life expectancy of ≥ 3 months. 9. Patients, both male and female, who are either not of childbearing potential or who agree to use a medically effective method of contraception during the study and for 3 months after the last dose of study drug. 10. Patients with the ability to understand and give written informed consent for participation in this trial, including all evaluations and procedures as specified by this protocol.
Exclusion criteria
-Patients: 1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP), and fertile men with a WOCBP-partner not using and not willing to use a medically effective method of contraception. 2. Patients with known central nervous system (CNS) or leptomeningeal metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required. 3. Patients with leukemia (any form) or myelodysplastic syndromes. 4. MTD PNET Cohort ONLY: Patients with poorly differentiated, high grade (grade 3) neuroendocrine carcinoma, as well as patients with adenocarcinoid, goblet cell carcinoid, or small cell carcinoma, or PNET patients with a Ki-67 proliferation index \> 20 %. 5. Patients with any of the following hematologic abnormalities at baseline: * Absolute neutrophil count \< 1,500 per mm3 * Platelet count \< 100,000 per mm3 6. Patients with any of the following serum chemistry abnormalities at baseline: * Total bilirubin \> 1.5 × the ULN for the institution * AST or ALT \> 3 × the ULN for the institution (\> 5 × if due to hepatic involvement by tumor) * Creatinine \> 1.5 × ULN for the institution 7. Patients with any of the following coagulation parameter abnormalities at baseline: * PT (INR) \> 1.5 × ULN for the institution * PTT \> 1.5 × ULN for the institution 8. Patients with: * Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 6 months prior to first study drug administration; patients receiving systemic anti-coagulation for prophylactic or therapeutic reasons * Active uncontrolled bleeding or a known bleeding diathesis 9. Patients with a significant cardiovascular disease or condition, including: * Congestive heart failure currently requiring therapy * Need for antiarrhythmic medical therapy for a ventricular arrhythmia * Severe conduction disturbance (e.g., 3rd degree heart block) * Angina pectoris requiring therapy * Known left ventricular ejection fraction \< 50% by MUGA or echocardiogram * QTc interval \> 450 msec in males, or \> 470 msec in females * Uncontrolled hypertension (per the Investigator's discretion) * Class III or IV cardiovascular disease according to the New York Heart Association's Functional Criteria. * Myocardial infarction within 6 months prior to first study drug administration 10. Patients with a known or suspected hypersensitivity to any of the components of lipid nanoparticle-formulated DCR-MYC. 11. Patients with a known history of human immunodeficiency virus or active infection with hepatitis B virus or hepatitis C virus. 12. Patients with any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever \> 38ºC within 2 weeks prior to first study drug administration. 13. Patients with inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy. 14. Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to first study drug administration. 15. Patients with any other life-threatening illness, significant organ system dysfunction, or clinically significant laboratory abnormality, which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with evaluation of the safety of the study drug. 16. Patients with a psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary study-related evaluations. 17. Patients with the inability or with foreseeable incapacity, in the opinion of the Investigator, to comply with the protocol requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with adverse events as a measure of safety and tolerability | Cycle 1 (3 weeks), longer if DRC-MYC is continued; with 30 days follow-up after last dose | Part A: 1 patient cohorts with 100% dose increase between cohorts until \>/= Grade 2 study drug-related toxicity during Cycle 1, then expand to 3 patients and move to Part B. Part B: 3 patient cohorts with 50% dose increase between cohorts until study drug-related DLT during Cycle 1, then expand to 6 patients and move to Part C. Part C: 3 to 6 patient cohorts with 25% dose increase between cohorts until \> 1 study drug-related DLT, then stop escalation and expand previous MTD cohort to 18 patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DCR-MYC levels in blood | Cycle 1; Week 1 and Week 2 | Samples to be collected Week 1 (Day 1, 2, and 4) and Week 2 (Day 8 and 11) |
| DCR-MYC biological activities | Cycle 1; Week 1 and Week 2 | Collection of blood samples for cytokine measurements Week 1 (Day 1, 2, and 4) and Week 2 (Day 8) |
| Preliminary antitumor activity | After Cycle 2 (6 weeks), then at 6 week intervals if DCR-MYC is continued | Evaluation for evidence of objective response or disease stabilization |
Countries
United States
Outcome results
None listed