Halperin7e_CH29

658

S E C T I O N I I  Techniques, Modalities, and Modifiers in Radiation Oncology

TABLE 29.5  FDA-APPROVED AND CURRENT PHASE III RIT DRUGS Drug Name Target

Targeting Construct

Radionuclide Disease

Pipeline

Company/Sponsor

90 Y 131 I

NHL (low-grade follicular) NHL (low grade follicular) Midgut neuroendocrine tumors

FDA 2002 FDA 2003

Biogen Idec

Zevalin (Ibritumomab Tiuxetan) IgG1 (Murine)

CD20 CD20

Bexxar a (Tositumomab) Lutathera ( 177 Lu–DOTATATE)

IgG2a (Murine)

GlaxoSmithKline

Octreotate peptide Somatostatin receptor

177 Lu

Phase III completed filing

Advanced Accelerator Applications

Zevalin

IgG1 (murine)

CD20

90 Y

Relapse DLBCL/ASC transplant

Phase III completed Sheba Medical Center

131I–chTNT

IgG1 chimeric murine

Histone H1/DNA

131 I

Non–small cell lung cancer (postoperative)

Phase III complete Guangxi Zhuang

Autonomous Region Self Financing Project, China

Licartin (131I–Metuximab)

F(ab’) 2

CD147

131 I

HCC with RFA

Phase III complete Biotechnology Chengdu, China

Zevalin

IgG1 (Murine)

CD20

90 Y

Relapsed follicular NHL/ consolidation Untreated follicular NHL

Phase III recruiting (NCT01827605) Phase III recruiting (NCT02320292) Phase III recruiting (NCT02665065) Phase III recruiting (NCT02465112) Phase III recruiting (NCT03049198)

Fondazione Italiana Linfomi

Zevalin

IgG1 (Murine)

CD20

90 Y

Mayo Clinic

Iomab-B (BC8-I-131)

IgG1 (Murine)

CD45

131 I

AML

Actinium Pharmaceuticals

111 In–Pentetreotide

Octreotate peptide Somatostatin receptor Octreotate peptide Somatostatin receptor

111 In

Resected GI neuroendocrine tumors

GERCOR

177Lu–Edotreotide

177 Lu

GEP-NET

ITM Solucin GmbH

a Withdrawn from production by GlaxoSmithKline in 2013.

pure β -particle emitter with a physical half-life of 2.7 days. The β -particle has an energy of 2.3 MeV and a maximum tis- sue penetration of approximately 12.0 mm (R 90 = 5.2 mm). Tiuxetan is a DTPA-type chelate that attaches 90 Y to the mAb, ibritumomab. Because there is no gamma emission in the spectrum of this isotope, it is not visualized by gamma cam- era scans. As a result, a biodistribution assessment cannot be performed. Therefore, a surrogate imaging radionuclide that emits gamma radiation 111 In is required. In contrast, 131 I tosi- tumomab is a mixed β - / γ -emitter. The gamma spikes at 364 keV, and the beta emission has energy of 0.6 MeV. The maxi- mum range in tissue of the β -particle is 2.3 mm (R 90 = 0.7 mm). This agent can be imaged on gamma camera to calculate total body clearance. For both agents, the treatment is delivered over 1 to 2 weeks. On day 1, both protocols deliver an infusion of nonradioactive (cold) anti-CD20 antibody (Zevalin employs rituximab; Bexxar employed tositumomab) designed to saturate the CD20 antigen sink (depletion of peripheral B cells and the binding of nonspecific sites in the liver and spleen) and provide antibody mass, which improves biodis- tribution and tumor targeting. 43,44 The administered activ- ity for Zevalin is based on weight (0.4 mCi/kg for a platelet count ≥150,000; 0.3 mCi/kg for a platelet count of 100,000 to 149,000; maximum of 32 mCi). A single gamma scan ( 111 In ibritumomab tiuxetan) is used to confirm a normal biodistri- bution on days 3 to 4. A review of the Zevalin imaging registry reveals that only 0.6% of scans exhibited an altered biodistri- bution. Subsequently, the delivery of Zevalin has been simpli- fied. Based upon the analysis of five trials, which revealed an altered biodistribution scan in only about 1% of patients, the FDA removed the requirement of the biodistribution scan.The administered activity for Bexxar was based on a calculated total body clearance (three scans over 1 week) that delivers a total-body (red bone marrow) dose of 75 cGy. This calcula- tion is reduced to a total-body dose of 65 cGy for a platelet count <150,000. Eligible patients for Zevalin are also required to have an absolute neutrophil count (ANC) ≥1,500 and a bone marrow biopsy that reveals <25% lymphoma involvement. Relapse Setting Multiple prospective clinical trials have provided evidence for the use of RIT for treating relapsed or refractory follicu- lar NHL. Together, they represent >200 patients treated with

either Zevalin or Bexxar. Both agents appear to suggest an overall response rate (ORR) of 60% to 80% and a CR rate of 20% to 50%. Zevalin trials have been extensively reviewed. 45,46 A phase III study comparing Zevalin versus rituximab for patients with relapsed or refractory low-grade follicular B-cell NHL or transformed NHL was performed. 47 Patients were ran- domized to either a single intravenous (IV) dose of Zevalin 0.4 mCi/kg ( n = 73) or IV rituximab 375 mg/m 2 weekly for four doses ( n = 70). The RIT group was pretreated with two ritux- imab doses (250 mg/m 2 ) to improve biodistribution and tumor targeting. After the first rituximab dose on day 1, 111 In ibritu- momab tiuxetan was administered to assess biodistribution and to aide in dosimetry. No patients received the therapeutic dose of 90 Y ibritumomab tiuxetan (Zevalin) if >20 or 3 Gy was calculated to any nontumor organ or the red marrow, respec- tively. Zevalin was administered after the second rituximab dose approximately 1 week (days 7 to 9) after the first dose of rituximab and ( 111 )In ibritumomab tiuxetan. The administered activity of Zevalin was capped at 32 mCi. Patients in both arms of the study received two prior chemotherapy regimens. The ORR was 80% for Zevalin and 56% for rituximab ( P = .002). The CR rates were 30% and 16% ( P = .04), respectively, in the Zevalin and rituximab group. Durable responses ≥6 months were 64% versus 47% ( P = .030) for Zevalin versus rituximab. The conclusion of the study was that RIT with Zevalin was well tolerated and resulted in statistically significant and clin- ically significant higher ORRs and CRs than rituximab alone. Frontline Therapy Considering the concerns about RIT for treating large bulky tumors (tumor penetration, overall required dose, nonuni- form dose distributions), bringing RIT into a frontline thera- peutic setting after induction chemotherapy and maximum cytoreduction would be the next logical direction. A phase III first-line indolent trial (FIT) of consolidation with Zevalin compared to no additional therapy after first remission was reported for follicular B-cell NHL. 48 Patients with CD20+ stage III/IV follicular B-cell NHL who achieved a PR or CR to induc- tion chemotherapy were randomized to Zevalin ( n = 208) or to the control arm, representing no further treatment ( n = 206). Prior to chemotherapy, patients had documented <25% bone marrow involvement. After induction chemotherapy, blood counts had to recover such that the ANC was ≥1.5, plate- lets were ≥150,000, and hemoglobin was ≥9. Patients in the