Moxetumomab Pasudotox-tdfk (Lumoxiti(TM)) and Either Rituximab (Rituxan(R)) or Ruxience for Relapsed Hairy Cell Leukemia

Background:

* Hairy cell leukemia (HCL) is an indolent cluster of differentiation-22 (CD22+) B-cell leukemia comprising 2% of all leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the United States (US). HCL variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the relapsed/refractory population due to its poor prognosis and response to standard purine analog chemotherapy. hairy cell leukemia variant (HCL-V) cells are cluster of Differentiation 25 (CD25)-negative and wild type for BRAF, so HCLv patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that express unmutated IGHV4-34 (Immunoglobulin Heavy Variable 4-34) are wild-type for BRAF, remain brightly CD22 positive, and confer a poor prognosis when treated with chemotherapy.
* Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin, which kills CD22+ cells by binding to CD22 via the (Fv) fragment, and induction of apoptotic cell death catalytic inhibition of protein synthesis in the cytosol.
* Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR) rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.
* Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting its complete response (CR) endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4 2.5%), and HUS (grade 3-4 6.3%), both reversible.
* Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL which can consistently eradicate minimal residual disease (MRD), and this is associated with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the treatment of adult patients with HCL.
* Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated by Moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-cluster of differentiation 20 (CD20) monoclonal antibody (Mab) rituximab or Ruxience to Moxetumomab pasudotox-tdfk.

Objective:

-To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab/Ruxience used at the planned dose level, in patients with HCL and HCLv.

Eligibility:

* HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1 month response, at least 1 other therapy.
* Need for treatment, either 1) absolute neutrophil count (ANC) <1/nL, 2) hemoglobin (Hgb) <10g/dL, 3) platelet (Plt) <100/nL, 4) symptomatic splenomegaly, or enlarging HCL mass > 2cm in short axis
* Serum creatinine < 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine clearance = (140-age)(kg weight)/(72 x Creatinine).
* No uncontrolled infection or cardiopulmonary dysfunction

Design:

* Phase I trial, two arm, non-randomized, dose escalation
* Administration:

* Patients 1-13: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30 min, Rituximab 375 mg/m\^2 iv, 50-400 mg/hr.
* Patients 14-26: Moxetumomab pasudotox-tdfk 40 mcg/kg intravenous (iv) over 30 min, Ruxience 375 mg/m2 iv, 50-400 mg/hr
* Rituximab or Ruxience day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk days 1, 3, and 5.
* Patients will receive up to 4 cycles past documentation of CR without MRD, maximum 8.
* To prevent renal toxicity and hypovolemia, patients will be encouraged to drink water gradually, approximately 0.5-1 cup/hour or 6L/day, not going >3 hours without drinking from days 1 to 8 and to keep a hydration diary to record daily fluid consumption.
* To prevent rituximab/Ruxience toxicity, patients will receive prophylactic dexamethasone orally 0.5- 2 hours before the 1st dose of rituximab, and before subsequent doses until rituximab/Ruxience infusion reactions are not seen. Patients will also receive diphenhydramine, famotidine, and acetaminophen.
* Dexamethasone 4 mg orally (maximum 2 doses/day) will be given as needed to treat nausea or fever associated with Moxetumomab pasudotox-tdfk, which might prevent adequate water intake
* Statistical design:

* Up to 26 patients are intended to be treated in the trial. While a total of 26 evaluable patients will be enrolled, the accrual ceiling will be set at 30 to include screen failures and inevaluable patients.

• Moxetumomab Pasudotox-tdfk (Drug), also known as Lumoxiti: Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg intravenous (iv) over 30 min given on days 1, 3, 5 of each cycle.
• Rituximab (Biological), also known as Rituxan: Rituximab will be administered at 375mg/m\^2 intravenous (iv), 50-400 mg/hour (hr). On cycle 1, Rituximab is given on day -2, on subsequent cycles, Rituximab is given on day 1.
• Ruxience (Biological), also known as Rituximab-pvvr: Ruxience will be administered at 375mg/m\^2 intravenous (iv), 50-400 mg/hour (hr). On cycle 1, Ruxience is given on day -2, on subsequent cycles, Ruxience is given on day 1 (Delta)
• Dexamethasone (Drug), also known as Ozurdex, Maxidex, DexPak 6 Day: 12 mg Cycle 1, Day -2; Cycles 2-8, Day 1. Administer 0.5-2 hours before rituximab/Ruxience. If participant has previous reaction to rituximab/Ruxience, give 12mg. If participants tolerate rituximab/Ruxience without problems, may hold at discretion of provider. Pre-medications are given prior to rituximab/Ruxience on day 1.
• Acetaminophen (Drug), also known as Tylenol, Ofirmev, FeverAll: 650 mg Cycle 1, Day -2, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and recommended every 6 hours x 4 after the end of infusion; Cycles 2-8, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and recommended every 6 hours x 4 after the end of infusion. Pre-medications are given prior to rituximab/Ruxience on day 1.
• Diphenhydramine (Drug), also known as Benadryl, Nytol, Banophen: 25-50 mg Cycle 1, Day -2; Cycles 2-8, Day 1. Pre-medications are given prior to rituximab/Ruxience on day 1. May be given prior to moxetumomab pasudotox-tdfk at discretion of principal investigator.
• Famotidine (Drug), also known as Pepcid AC, Pepcid, Acid Controller: 20-40 mg Cycle 1, Day -2; Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and is recommended every 12 hours x 2 after the end of infusion; Cycles 2-8, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and is recommended every 12 hours x 2 after the end of infusion. Pre-medications are given prior to rituximab/Ruxience on day 1.
• Aspirin (Drug), also known as Ecotrin, Enteric Coated Aspirin, Buffered Aspirin: 81 mg Cycle 1, Days 1-8; Cycles 2-8, Days 1-8. Only if platelet counts ≥ 100 x 109/L.

Primary outcomes

• Recommended Safe Dose of Moxetumomab Pasudotox-tdfk [4 weeks]: Recommended safe dose of moxetumomab pasudotox-tdfk is defined as the treatment of 10 participants with no more than 2 experiencing a dose-limiting toxicity (DLT). A DLT is defined as all treatment related Grade 3-5 adverse events (AEs) occurring from the initiation of moxetumomab pasudotox-tdfk therapy to within 30 days after the last dose of moxetumomab pasudotox-tdfk treatment assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
• Recommended Safe Dose of Rituximab/Ruxience [4 weeks]: Recommended safe dose of rituximab/Ruxience is defined as the treatment of 10 participants with no more than 2 experiencing a dose-limiting toxicity (DLT). A DLT is defined as all treatment related Grade 3-5 adverse events (AEs) occurring from the initiation of moxetumomab pasudotox-tdfk therapy to within 30 days after the last dose of moxetumomab pasudotox-tdfk treatment assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.

Secondary outcomes

• Number of Participants Whose Cancer Shrinks or Disappears After Treatment [28-42 days after day 1 of the last treatment.]: Number of participants whose cancer shrinks or disappears after treatment defined as minimal residual disease. MRD is no hairy cell leukemia (HCL) in the blood and bone marrow aspirate flow determined by immunohistochemistry (IHC) and flow cytometry of blood and bone marrow aspirate.
• Number of Participants Who Are Minimal Residual Disease (MRD)-Free [28-42 days after day 1 of the last treatment.]: MRD-free is defined as participants with no hairy cell leukemia (HCL) in the blood and bone marrow aspirate flow determined by immunohistochemistry (IHC) and flow cytometry of blood and bone marrow aspirate.
• Duration of Response (DOR) [28-42 days after day 1 of the last treatment.]: DOR is defined as the time of initial response until documented tumor progression. Response was assessed by the and is defined as an increase in symptoms or >25% decline in hematologic parameters related to disease, based on the judgement of the principal investigator. ≥50% increase in sum of products of perpendicular diameters of evaluable (> 2cm) lymphadenopathy or appearance of new evaluable lymph nodes > 2 cm short axis.

Other outcomes

• Number of Participants With a Dose-limiting Toxicity (DLT) [From the initiation of moxetumomab pasudotox-tdfk therapy to within 30 days after the last dose]: Dose limiting toxicity (DLT) is defined as all treatment related Grade 3-5 adverse events (AEs) occurring from the initiation of moxetumomab pasudotox-tdfk therapy to within 30 days after the last dose of moxetumomab pasudotox-tdfk treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) [Date treatment consent signed to date off study, approximately 11 months and 13 days for the first group, and 4 months and 3 days for the second group.]: Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Sex: All, ages: 18 Years to any

* INCLUSION CRITERIA:
* Diagnosis of hairy cell leukemia (HCL) or Hairy cell leukemia variant (HCLv).
* Treatment required for either 1) Absolute neutrophil count (ANC) <1/nL, 2) Hemoglobin <10g/dL, 3) Platelets<100/nL, 4) symptomatic splenomegaly, or 5) enlarging HCL mass > 2cm in short axis. Patients who have eligible blood counts within 4 weeks from the initiation of study will not be considered ineligible if subsequent blood counts prior to enrollment fluctuate and become ineligible up until the time of enrollment.
* Patients must be Pseudomonas-immunotoxin naive.
* HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1 month response, at least 1 other therapy. Age greater than or equal to 18 years as the disease under study, HCL/HCLv, has not been reported in children < age 18.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to2 (Karnofsky greater than or equal to 60%)
* Patients must have adequate organ and marrow function as defined below:

  * Total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert's (ratio between total and direct bilirubin > 5)
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3x upper limit of normal (ULN)
  * Alkaline phosphatase < 2.5 ULN
  * Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine clearance = (140-age)(Kg weight)/(72 x Creatinine)
  * Serum albumin greater than or equal to 2 g/dL
  * Partial thromboplastin time (PTT) or Prothrombin time (PT)/International Normalized Ratio < 2.5x ULN (If on warfarin, PT/INR < 3.5x ULN; If on any other anticoagulation, Prothrombin time (PT) < 2.5x baseline)
  * Fibrinogen greater than or equal to 0.5 lower limit of normal
* The effects of moxetumomab pasudotox-tdfk and rituximab/Ruxience on the developing human fetus are unknown therefore participants must use effective methods of contraception as directed below.

  * Females of childbearing potential (< 50 years) who are sexually active with a non-sterilized male partner must use a highly effective method of contraception prior to study entry and or the duration of study participation and must agree to continue using such precautions for 12 months after completion of rituximab/Ruxience administration. Contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who are premenarchal or postmenopausal (defined as 12 months with no menses without an alternative medical cause). A highly effective method of contraception is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Not all methods of contraception are highly effective. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  * Non-sterilized males who are sexually active with a female partner of childbearing potential must use an effective method of contraception from Day 1 until 90 days after receipt of the final dose of investigational product. It is required that a female partner of a male subject also use an effective method of contraception throughout this period.
* Ability of subject to understand and the willingness to sign a written informed consent document.
* Patients must be willing to co-enroll in the investigators companion protocol 10C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias, and to Develop Recombinant Immunotoxins for Cancer Treatment.

EXCLUSION CRITIERIA:

* Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks or treatment with rituximab/Ruxience within last 3 months prior to initiation of treatment.
* Patients who are receiving any other investigational agents.
* Breastfeeding within the projected duration of the study, starting with the screening visit through 6 months after the last dose of rituximab/Ruxience. Pregnant women are excluded from this study because moxetumomab pasudotox-tdfk and rituximab/Ruxience are agents with 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 moxetumomab pasudotox-tdfk and rituximab/Ruxience, breastfeeding should be discontinued if the mother is treated with moxetumomab pasudotox-tdfk and rituximab/Ruxience.
* Patients with known brain metastases 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.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, uncontrolled pulmonary infection, pulmonary edema or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients with retinal or choroidal detachment.
* Positive for Hepatitis B core antibody or surface antigen unless the patient is on Tenofovir or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load is <2000 IU/mL
* Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers.
* Human immunodeficiency virus (HIV)-positive patients unless taking appropriate anti-HIV medications with a cluster of differentiation 4 (CD4) count of > 200. Otherwise, there may be an increased risk of lethal infections when temporarily suppressing normal B-cells.
* History of an allogeneic bone marrow transplant.
* Patients with a history of both thromboembolism and known congenital hypercoagulable conditions.
* Radioimmunotherapy within 2 years prior to enrollment in the study.
* Patients with history of thrombotic microangiopathy or thrombotic microangiopathy/hemolytic uremic syndrome (HUS).
* Patients with corrected QT interval (Frederica) elevation > 500 msec (manually over-read by medically qualified person) based on at least two separate 12-lead ECGs.
* Patients on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound).
* Oxygen saturation at rest < 88% measured by pulse oximetry or partial pressure of oxygen (PaO2) less than or equal to 55 mm Hg.
* Patients with life expectancy of less than 6 months.
* Patients with clinical evidence of disseminated intravascular coagulation (Grade 3-4).
* Patients with < 50% of predicted forced expiratory volume (FEV1) or < 50% of predicted diffusing capacity for carbon monoxide, corrected for hemoglobin concentration and alveolar volume (DLCO). Note: Patients with no prior history of pulmonary illness are not required to have pulmonary function testing (PFT). Forced expiratory volume will be assessed after bronchodilator therapy.

Participant flow

Outcome results

• Recommended Safe Dose of Moxetumomab Pasudotox-tdfk (Primary), Number, mcg/kg: All Participants 40
• Recommended Safe Dose of Rituximab/Ruxience (Primary), Number, mcg/kg: All Participants 40
• Number of Participants Whose Cancer Shrinks or Disappears After Treatment (Secondary), Count of participants, Participants: Moxetumomab - Dose Escalation 30 mcg/kg 2; Moxetumomab - Dose Expansion 40 mcg/kg 11
• Number of Participants Who Are Minimal Residual Disease (MRD)-Free (Secondary), Count of participants, Participants: Moxetumomab - Dose Escalation 30 mcg/kg 2; Moxetumomab - Dose Expansion 40 mcg/kg 11
• Duration of Response (DOR) (Secondary)
• Number of Participants With a Dose-limiting Toxicity (DLT) (Other pre specified), Count of participants, Participants: Moxetumomab - Dose Escalation 30 mcg/kg 0; Moxetumomab - Dose Expansion 40 mcg/kg 0
• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0) (Other pre specified), Count of participants, Participants: Moxetumomab - Dose Escalation 30 mcg/kg 3; Moxetumomab - Dose Expansion 40 mcg/kg 15

Adverse events

Time frame: Date treatment consent signed to date off study, approximately 11 months and 13 days for the first group, and 4 months and 3 days for the second group.

Serious adverse events by term

Other adverse events by term

39 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2025-04-16)
• Informed Consent Form (PDF, 2025-05-16)

• Robert J Kreitman, M.D., Principal investigator, National Cancer Institute (NCI)