Leukemia Clinical Trials
A Phase 2, Multicenter, Single-arm Study of Zanubrutinib (BGB-3111) in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Intolerant of Prior Treatment with Ibrutinib
Treatment Agent: Zanubrutinib
Synopsis: You are being asked to take part in this study because you have been diagnosed with a cancer called Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).
The purpose of this study is to study the safety and efficacy of the study drug zanubrutinib (also known as BGB-3111) in Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) patients who discontinued prior ibrutinib treatment due to toxicities.
Zanubrutinib is an experimental drug. This means that it has not been approved for use by the regulatory agencies in any country, but it can be used in research studies such as this one. As of September 2018, zanubrutinib has been given to approximately 1200 participants who are taking or have taken part in research studies with zanubrutinib as a single drug or in combination with another anticancer drug.
Zanubrutinib blocks a protein called Bruton Tyrosine Kinase (BTK). BTK helps CLL/SLL cells live and grow. By blocking BTK, zanubrutinib is capable of stopping or slowing down the growth and activity of CLL/SLL cells, which can lead to improvement in the symptoms associated with CLL/SLL. However, not all patients will improve to the same degree, and some patients might not improve at all.
- Age 18 years or older receiving treatment with ibrutinib for a minimum of 4 weeks prior to enrollment
- CLL or SLL that meets diagnostic criteria and requires treatment by 2008 iwCLL criteria prior to initiation of ibrutinib.
- Intolerant to ibrutinib
- Ibrutinib-related toxicities must have resolve to Grade ≤ 1 or baseline prior to initiating treatment with zanubrutinib
- ECOG performance status ≤ 2
- Adequate bone marrow function
- Adequate renal and hepatic function
- Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation
- Intervening anticancer therapy after discontinuation of ibrutinib and prior to initiation of zanubrutinib
- Clinically significant cardiovascular disease
- History of ischemic stroke within 180 days before first dose of zanubrutinib
- History of CNS hemorrhage
- Prior malignancy within the past 3 years, except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast
- History of inherited or acquired hemorrhagic coagulopathy
- Unable to swallow capsules, or disease significantly affecting gastrointestinal function such as malabsorption syndrome, resection of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
- Active fungal, bacterial, and/or viral infection requiring systemic therapy
- Known CNS involvement by leukemia or lymphoma
- Documented progressive disease (PD) during ibrutinib treatment up to the time of enrollment
- Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs
- Known infection with HIV or active viral hepatitis B or C infection
- History of opportunistic infection while on ibrutinib
- Major surgery within 4 weeks of the first dose of study drug
- Pregnant or lactating women
- Ongoing alcohol or drug addiction
- Prior exposure to zanubrutinib or hypersensitivity to zanubrutinib formulation excipients
- Concurrent participation in another therapeutic clinical trial
A Phase 3, Randomized, Controlled, Open-label, Clinical Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
Lauren Downing, BS, CCRP
Treatment Agent: Pevonedistat
Synopsis: The purpose of this research study is to evaluate pevonedistat in combination with azacitidine in patients with higher-risk MDS, CMML, and low-blast AML. If you choose to participate in this study, you will be treated with azacitidine. Azacitidine is a widely used treatment for patients with these diseases. In addition, you may also be treated with the investigational drug pevonedistat. An investigational drug means that the FDA (U.S. Food and Drug Administration) and other regulatory authorities have not approved the drug. Pevonedistat is currently being studied in humans with advanced solid tumors, higher-risk MDS, CMML, and acute myelogenous leukemia (AML). This study will assess whether taking pevonedistat in combination with azacitidine increases the amount of time you live without any worsening of your disease when compared to azacitidine alone.
- Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or nonproliferative chronic myelomonocytic leukemia (CMML) (i.e., with white blood cell [WBC] <13,000/μL) or low-blast acute myelogenous leukemia (AML).
- Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
- Very high (>6 points).
- High (>4.5-6 points).
- Intermediate (>3-4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
- Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2.
- Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers.
- Calculation of TRM score:
- 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years).
- + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
- + 0 for (platelets <50), +1 for (platelets >50).
- Has previous treatment for higher-risk myelodysplastic syndromes (HR MDS) or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
- Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.
- Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
- Age >75.
- Inability to tolerate intensive chemotherapy (e.g., patients with AML with 20%-30% blasts and TRM ≥4).
- Physician decision (e.g., lack of available stem cell donor).
- The reason a participant is not eligible should be documented in the electronic case report form (eCRF).
- Has either clinical evidence of or history of central nervous system involvement by AML.
- Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
- Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease.
- Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection.
- Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
- Has known human immunodeficiency virus (HIV) seropositive.
- Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load.
- Has known hepatic cirrhosis or severe preexisting hepatic impairment.
- Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension.
- Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.
A Phase 3b, Multicenter, Open-Label, Single-Arm Study of Acalabrutinib (ACP-196) in Subjects with Chronic Lymphocytic Leukemia
Treatment Agent: Acalabrutinib
Synopsis: AstraZeneca is doing this research study to find out if the experimental medication called acalabrutinib will work and be safe for the treatment of CLL. Acalabrutinib is a type of drug that blocks proteins inside cells that help cells live and grow. The protein blocked by the study drug is believed to help blood cancer cells live and grow. It is possible that the study drug may kill the cancer cells or stop them from growing. Acalabrutinib is an approved drug for the treatment of adult subjects with mantle cell lymphoma, but it is not approved for treatment of CLL except for use in research studies like this. Your hospital/clinic/doctor are being paid by AstraZeneca to do the research. AstraZeneca AB, S-151 85, Sodertalje, Sweden is responsible for your personal information and any results from research described in this document is owned by AstraZeneca AB.
- Men and women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place)
- Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018):
- Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥1 B-cell marker (CD19, CD20, and CD23) and CD5
- Prolymphocytes may comprise <55% of blood lymphocytes
- Presence of ≥5 × 109 B lymphocytes/L (5000/μL) in the peripheral blood (at any point since the initial diagnosis)
- Active disease as per at least 1 of the following IWCLL 2018 criteria
- Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (platelets <100,000/μL).
- Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
- Massive nodes (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy
- Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte count obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of <30x109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
- B-symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥1 of the following disease-related symptoms or signs: o- Unintentional weight loss ≥10% within the previous 6 months before screening o- Significant fatigue (Eastern Cooperative Oncology Group [ECOG] performance status ≥2; inability to work or perform usual activities) o- Fevers higher than 100.5°F or 38.0°C for ≥2 weeks before screening without evidence of infection o- Night sweats for ≥1 month before screening without evidence of infection
- Must meet 1 of the following criteria:
- Have received no prior therapy for treatment of CLL and meets 1 of the following criteria:
- A score of >6 on the Cumulative Illness Rating Scale (CIRS)
- Creatinine clearance of 30 to 69 mL/min using the Cockcroft-Gault equation
- Have previously received therapy for CLL and have either refractory or relapsed CLL
- Have received prior BTKi therapy (i.e., defined as a subject who discontinued a BTKi for any reason except disease progression) for CLL d. Criterion deleted.
- Have received no prior therapy for treatment of CLL and meets 1 of the following criteria:
- ECOG performance status of ≤2
- Female subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) who are sexually active with a non-sterilized male partner must use ≥1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 2 days after the last dose of study treatment. Contraception measures and restrictions on sperm donation are not required for male subjects.
- Fluorescence in situ hybridization (FISH) within 60 days before or during screening reflecting the presence or absence of del(17p), 13q del, 11q del, and trisomy of chromosome 12 along with the percentage of cells with the deletion, along with TP53 sequencing. Subjects must also have molecular analysis to detect IGHV mutation status at any time point since diagnosis.
- Each subject (or legally authorized representative if allowed per local regulations) must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
- Subjects who have had disease progression while on a BTKi for any malignant or nonmalignant condition
- Prior malignancy (other than CLL), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, early stage prostate cancer, or other cancer from which the subject has been disease-free for ≥2 years
- History of confirmed progressive multifocal leukoencephalopathy
- Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval using Fridericia's formula (QTcF) >480 msec at screening. Note: Subjects with rate-controlled, asymptomatic atrial fibrillation are allowed to enroll in the study.
- Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
- Evidence of active Richter's transformation. If Richter's transformation is suspected (i.e., lactate dehydrogenase [LDH] increased, asymmetric fast lymph node growth or clinical suspicion), it should be ruled out with positron emission tomographycomputed tomography (PET-CT) and/or biopsy according to guidelines.
- Central nervous system (CNS) involvement by CLL.
- Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus or hepatitis C virus infection, any uncontrolled active systemic infection along with subjects who are on ongoing anti-infective treatment and subjects who have received vaccination with a live attenuated vaccine within 4 weeks before the first dose of study treatment.
- Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antibody (anti-HBs) negative will need to have a negative hepatitis B virus PCR result before enrollment. Those who are hepatitis B surface antigen (HBsAg) positive or hepatitis B virus PCR positive will be excluded.
- Subjects who are hepatitis C virus antibody positive will need to have a negative hepatitis C virus PCR result before enroll.lment. Those who are hepatitis C virus PCR positive will be excluded
- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (>20 mg daily of prednisone or equivalent for longer than 2 weeks).
- History of stroke or intracranial hemorrhage within 6 months before the first dose of study treatment.
- History of bleeding diathesis (e.g., hemophilia or von Willebrand disease)
- Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
- Major surgical procedure within 4 weeks before first dose of study treatment. Note: Subjects who have had major surgery must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study treatment.
- Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
- All subjects requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days before first dose of study treatment.
- Absolute neutrophil count (ANC) <0.50 x 109/L or platelet count <30 x 109/L, unless proven due to CLL and raised above the limits by granulocyte colony-stimulating factor (G-CSF) therapy and/or pooled platelet transfusion
- Total bilirubin >3.0x upper limit of normal (ULN); or aspartate aminotransferase or alanine aminotransferase >3.0x ULN. Exception will be for Gilbert syndrome; if an investigator feels that a subject's total bilirubin is elevated secondary to Gilbert's, the subject must have a documented unconjugated bilirubin being >80% of the total bilirubin number. The investigator must also document that hemolysis has been ruled out along with (near)-normal lactate dehydrogenase and haptoglobin
- Estimated creatinine clearance of <30 mL/min, calculated using the formula of Cockcroft and Gault or by direct assessment (i.e., creatinine clearance or ethylene diamine tetra-acetic acid (EDTA) clearance measurement)
- Breastfeeding or pregnant
- Received any chemotherapy, external beam radiation, investigational drug, or any other anti-CLL therapy within 30 days before first dose of study treatment
- Concurrent participation in another therapeutic clinical study
- History of interstitial lung disease
- Requiring long-term (> 1 week) treatment with a strong cytochrome CYP3A inhibitor/inducer. In addition, the use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.