Anti-CD20 Radioimmunotherapy Before Chemotherapy and Stem Cell Transplant in Treating Patients With High-Risk B-Cell Malignancies

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) of 90Y activity that can be delivered via pretargeted radioimmunotherapy (PRIT) using B9E9-fusion protein (B9E9-FP), clearing agent (CA), and radiolabeled tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin when followed by carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and autologous stem cell transplantation.

SECONDARY OBJECTIVES:

I. To assess the overall and progression-free survival of the above regimen in such patients.

II. To evaluate the response rates of the above therapy.

III. To evaluate the toxicity and tolerability of the above therapy.

IV. To evaluate the feasibility of delivering sequential high-dose PRIT and chemotherapy.

TERTIARY OBJECTIVES:

I. Assess biodistribution and pharmacokinetics of B9E9-FP and radiolabeled DOTA-Biotin.

II. Assess ability of the clearing agent (CA) to remove excess B9E9-FP from the serum.

III. Evaluate the impact, if any, of circulating rituximab on biodistributions.

OUTLINE: This is a phase I, dose-escalation study of yttrium Y 90 DOTA-biotin followed by a phase II study.

B9E9-FP INFUSION: Patients receive B9E9-fusion protein intravenously (IV) over a minimum of 2 hours on day -17.

CLEARING AGENT INFUSION: Patients receive clearing agent IV over a minimum of 30 minutes on day -15.

RADIOBIOTIN INFUSION: Patients receive indium In 111-DOTA-biotin IV and yttrium Y 90 DOTA-biotin IV over 2-5 minutes on day -14.

BEAM CHEMOTHERAPY: Patients receive BEAM chemotherapy comprising carmustine IV over 3 hours on day -7; etoposide IV over 2 hours twice daily (BID) and cytarabine IV over 4 hours BID on days -6 to -3; and melphalan IV over 30 minutes on day -2.

STEM CELL INFUSION: Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0 per standard of care.

After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months, and then annually thereafter.

• Anti-CD20 B9E9 scFv-Streptavidin Fusion Protein (Biological), also known as Anti-CD20 B9E9 scFv-SA Fusion Protein, Anti-CD20 B9E9-SA Fusion Protein, B9E9 scFvSA Fusion Protein, Recombinant Anti-CD20 B9E9 scFvSA Fusion Protein, scFv B9E9-streptavidin Fusion Protein: Given IV
• Autologous Hematopoietic Stem Cell Transplantation (Procedure), also known as Autologous Stem Cell Transplantation: Undergo autologous PBSCT
• Carmustine (Drug), also known as BCNU, Becenum, Becenun, BiCNU, Bis(chloroethyl) Nitrosourea, Bis-Chloronitrosourea, Carmubris, Carmustin, Carmustinum, FDA 0345, Gliadel, N,N'-Bis(2-chloroethyl)-N-nitrosourea, Nitrourean, Nitrumon, SK 27702, SRI 1720, WR-139021: Given IV
• Clearing Agent (Drug): Given IV
• Cytarabine (Drug), also known as .beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosar-U, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453: Given IV
• Etoposide (Drug), also known as Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213: Given IV
• Indium In 111-DOTA-Biotin (Radiation), also known as In 111-DOTA-Biotin: Given IV
• Laboratory Biomarker Analysis (Other): Correlative studies
• Melphalan (Drug), also known as Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813: Given IV
• Peripheral Blood Stem Cell Transplantation (Procedure), also known as PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation: Undergo autologous PBSCT
• Pharmacological Study (Other): Correlative studies
• Yttrium Y 90-DOTA-Biotin (Radiation), also known as 90Y-DOTA-Biotin, yttrium Y 90 DOTA-biotin: Given IV

Primary outcomes

• Maximum Tolerated Dose (MTD) of Yttrium Y 90 DOTA-biotin Defined as the Dose That is Associated With a True Dose Limiting Toxicity (DLT) Rate of 25%, Where a DLT is Defined as a Therapy-related Grade III or IV Bearman (Transplant) Toxicity [Up to 30 days after transplant]: Following the completed observation of the final patient, a two-parameter logistic model will be fit to the data, thereby generating a dose-toxicity curve based on the observed DLT rate at the various dose levels visited. Based on this fitted model, the MTD is estimated to be the dose that is associated with a DLT rate of 25%.

Secondary outcomes

• Dosimetry of Yttrium Y 90 DOTA-biotin [Up to 7 days after infusion]: Assessed using OLINDA dosimetry software. The estimated dose to normal organs and tumor sites will be described based on the tumor to normal organ ratios derived from dosimetry estimates coupled with the absorbed dose to normal organs based on the administered activity of yttrium Y 90 DOTA-biotin.
• Incidence of Toxicity, Defined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Up to 30 days after transplant]: Descriptive statistics on the number and percent toxicities will be calculated.
• Overall Response Rate [Up to 4 years]: Descriptive statistics on the responses will be calculated.
• Overall Survival [Up to 4 years]: Overall survival will be estimated.
• Progression Free Survival (PFS) [1 year from autologous stem cell transplant]: If the true 1-year PFS rate using the proposed approach is 54%, then 24 patients will provide 80% power to detect a statistically significant increased rate of PFS from the fixed rate of 30%, based on a one-sample chi-square test with one-sided significance level of 5%.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients must have a histologically confirmed diagnosis of lymphoma expressing the CD20 antigen and generally must have failed at least one prior standard systemic therapy; the exception will be mantle cell lymphoma (MCL) patients, who may be enrolled while in first complete remission (CR) as well as other select high-risk lymphomas (e.g., Burkitt?s, double hit diffuse large B-cell lymphoma \[DLBCL\], transformed indolent B-cell non-Hodgkin lymphoma \[B-NHL\], etc.) in accordance with current transplant standard of care for these patients
* Creatinine (Cr) < 2.0
* Bilirubin < 1.5 mg/dL, with the exception of patients thought to have Gilbert?s syndrome, who may have a total bilirubin above 1.5 mg/dL
* All patients eligible for therapeutic study must have (>= 2 x 10\^6 CD34/kg) autologous hematopoietic stem cells harvested and cryopreserved
* Patients must have an expected survival of > 60 days and must be free of major infection
* Patients of childbearing potential must agree to abstinence or the use of effective contraception
* DONOR SELECTION: Not applicable; this protocol employs autologous transplantation, utilizing the patient?s own hematopoietic stem cells obtained from either the peripheral blood or bone marrow

Exclusion Criteria:

* Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled 90Y therapy dose
* Inability to understand or give an informed consent
* Prior radiation > 20 Gy to any critical normal organ (e.g., lung, liver, spinal cord, both kidneys) within 1 year of the treatment date
* Active central nervous system lymphoma
* Other serious medical conditions considered to represent contraindications to bone marrow transplant (BMT) (e.g., abnormally decreased cardiac ejection fraction, diffusion capacity of the lung for carbon monoxide \[DLCO\] < 50% predicted, patient on supplemental oxygen, acquired immune deficiency syndrome \[AIDS\], etc.)
* Pregnancy or breast feeding
* Prior bone marrow or stem cell transplant
* Southwest Oncology Group (SWOG) performance status >= 2.0
* Known sensitivity to kanamycin and other aminoglycosides; patients with known hypersensitivity to kanamycin or any other aminoglycoside antibiotic will be excluded

Participant flow

Outcome results

• Maximum Tolerated Dose (MTD) of Yttrium Y 90 DOTA-biotin Defined as the Dose That is Associated With a True Dose Limiting Toxicity (DLT) Rate of 25%, Where a DLT is Defined as a Therapy-related Grade III or IV Bearman (Transplant) Toxicity (Primary)
• Dosimetry of Yttrium Y 90 DOTA-biotin (Secondary), Median, cGy/mCi: Treatment (PRIT) 2.5 (1.83 to 2.61)
• Incidence of Toxicity, Defined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Secondary), Count of participants, Participants: Treatment (PRIT) 2
• Overall Response Rate (Secondary), Count of participants, Participants: Treatment (PRIT) 2
• Overall Survival (Secondary), Count of participants, Participants: Treatment (PRIT) 2
• Progression Free Survival (PFS) (Secondary)

Adverse events

Time frame: AEs will be collected from the time of first exposure to an investigational agent through the start of BEAM chemotherapy treatment all SAEs and all grades of adverse events will be captured. From the start of BEAM chemotherapy through day +30 post-transplant non-hematologic adverse events of ≥ grade 3, and all serious adverse events will be captured. Beyond day +30 after transplant/discharge from the transplant service until day +100, only SAEs and grade 4 and 5 toxicities will be collected.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-05-24)

• Ajay Gopal, Principal investigator, Fred Hutch/University of Washington Cancer Consortium

NIH grants: P01CA044991, P30CA015704