Iomab-B (I-131-apamistamab)

P1/2, N=30, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Oct 2025 --> Mar 2027 | Trial primary completion date: Jan 2024 --> Jun 2025

Pts were randomized (1:1, N=153) to CC or Iomab-B with fludarabine and total body irradiation (2 Gy) followed by HCT (CC, n=77; Iomab-B, n=76). 131I-apamistamab led HCT significantly improves outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53 in terms of CR, dCR and OS , overcoming the negative impact of this mutation. These data support the use of 131I-apamistamab led induction/conditioning and HCT in R/R AML, especially in patients with a TP53 mutation.

Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.

Patients >55 years of age with R/R AML were randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy), and alloHSCT or CC (physician's choice of therapy, including targeted agents and alloHSCT if leukemia-free). Patients with failure of targeted therapies, including venetoclax, were able to undergo alloHSCT with the Iomab-B–led regimen. Of those who achieved dCR with Iomab-B, >70% had previous targeted-therapy failure, including >50% with previous venetoclax failure. The majority of dCR patients were long-term survivors.

For instance, the theranostic armamentarium for the referring hematooncologist now includes Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia...As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Recent prospective data from the phase III ASAP Trial also suggest that in patients with poor response after initial first induction therapy or relapsed AML watchful waiting and sequential conditioning prior to allogeneic HCT result in comparable CR rates as could be observed with salvage chemotherapy with high-dose cytarabine plus anthracycline...Early HLA-typing of AML patients and their family members (possibly at the time of diagnosis), conditioning regimens incorporating novel agents, such as briquilimab or 131I-apamistamab, engineered donor grafts and maintenance therapy with novel agents or cell therapeutics have the potential to improve disease-free and overall survival in this patient population through improved disease control...Allogeneic HCT should be considered in this patient population, preferably in the context of a clinical trial testing novel treatment modalities. Updated prognostic score systems have the potential to identify subgroups of patients deriving the most benefit from these approaches.

Mycophenolate mofetil was switched to everolimus, and he was referred to dermatology...Before he could pursue recommended treatments, he was admitted in November 2021 for fever, worsening back pain, leukocytosis (WBC 131.6 thousand/µL; increased from 7.3 thousand/µL in October 2021), anemia (6 gm/dL), and thrombocytopenia (17 thousand/µL)... Chronic immunosuppression impairs anti-tumor immune surveillance and has a central role in oncogenesis after solid organ transplant. LT recipients receive even more immunosuppression. Immunosuppression modification with mammalian target of rapamycin inhibitors (everolimus) may interfere with cancer cell proliferation and angiogenesis.

P1/2, N=30, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Sep 2024 --> Oct 2025 | Trial primary completion date: Sep 2023 --> Jan 2024

Within the last year alone, the FDA approved brexu-cel for adults w/ R/R B-ALL and expanded indications for liso-cel and axi-cel to include DLBCL w/ primary refractory disease or early first relapse...Anti-cytokine therapies beyond tocilizumab (anti-IL-6R mAb) are being investigated for prevention of CRS/ICANS, including lenzilumab (anti-GM-CSF mAb) and anakinra (IL-1R antagonist)...Accordingly, we designed and initiated a pilot study of Iomab-B w/ adoptive cellular therapy (Iomab-ACT; Fig 1A).Study design and Iomab-ACT is a single-institution pilot study of Iomab-B (w/o chemotherapy) as conditioning prior to 19-28z CAR-T in adults w/ R/R B-ALL or DLBCL (NCT04512716)...Unexpected toxicity (given low dose of ARC) observed in 1 pt included severe trilineage cytopenias lasting >8 wks (requiring RBC/PLT transfusion support, G-CSF, romiplostim) w/o marrow hypoplasia and w/o other apparent neoplastic or drug-induced etiology; this met criteria for dose-limiting toxicity and we will monitor in the next 3 pts...Key exploratory objectives include describing changes in circulating immune cells following ARC and 19-28z CAR T-cells w/spectral cytometry using a custom antibody panel (Fig 1B) and cytokine levels in cerebrospinal fluid. We hope to generate preliminary data to guide further study of CD45-targeted ARCs prior to CAR-T and other forms of adoptive cellular therapy.

An I-labeled CD45 antibody (Iomab-B [apamistamab-I131]) is currently studied in the registration-type phase 3 SIERRA trial (NCT02665065) for this purpose...Clinical efforts with At-labeled CD45 antibodies and Ac-labeled CD33 antibodies (e.g. Ac-lintuzumab [Actimab-A]) are ongoing. A first anti-AML RIT may soon become available. This might propel further work to develop RIT-based treatments for AML, with many such efforts already ongoing.

P3, N=153, Active, not recruiting, Actinium Pharmaceuticals | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2021 --> Jun 2022

Background: Complete remission (CR) rates in relapsed refractory (R/R) AML patients remain low despite treatment with recently approved targeted therapies (TT) like BCL-2 (venetoclax), FLT-3 and IDH inhibitors... R/R AML patients were randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy) and allogeneic HCT, or to conventional care (CC)... Iomab-B based conditioning allowed majority of patients to undergo HCT despite not achieving CR after standard and targeted therapies. All evaluable patients receiving Iomab-B based conditioning successfully engrafted. Patients receiving Iomab-B and HCT had lower rates of sepsis compared to those in the CC group receiving standard allogeneic HCT.

P1, N=26, Terminated, Fred Hutchinson Cancer Research Center | Active, not recruiting --> Terminated; Terminated due to loss of funding