AML, ALL, and Glioblastoma Multiforme Clinical Trials Seek to Push the Needle Forward

Leland Metheny, MD

Innovative clinical trials exploring pharmacokinetics and low-dose therapy with agents are at the forefront of investigations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and glioblastoma multiforme, according to Leland Metheny, MD.

Two currently enrolling trials include the phase 1 CASE4919 study (NCT04187703) which is looking at cycling 50 mg/m2 of azacitidine on day 1 with 5 mg/m2 of decitabine on day 4 weekly in patients with myelodysplastic syndromes (MDS) and the phase 1/2 CASE1916 study (NCT03104491) which is examining low-intensity therapy with inotuzumab ozogamicin (Besponsa) in patients with ALL.^1,2

Further, in the phase 3 SIERRA trial (NCT02665065) 74.6% of patients with relapsed or refractory AML who received the anti-CD45 radioimmunoconjugate Iomab-B (131I-apamistamab; n = 59) achieved initial complete remission (CR)/CR of 6 months or greater with or without platelet recovery vs 6.3% with physician’s choice of conventional care (n = 64).^3,4

Metheny discussed how agents such as Iomab-B have the potential to shift practice in the hematologic malignancy space in an interview with OncLive®, detailing ongoing clinical trials. He also detailed new treatment innovations centering around CAR T-cell therapy in non-Hodgkin lymphoma and multiple myeloma in an additional interview. Metheny is an assistant professor of medicine at Case Western Reserve University School of Medicine and member of the Immune Oncology Program at Case Comprehensive Cancer Center, as well as a hematologist/oncologist at University Hospitals Cleveland Medical Center in Ohio.

OncLive: What studies are currently ongoing in AML?

Metheny: [There are] 2 studies not necessarily focused on cellular therapy, but on a unique feature of pharmacokinetics between 2 agents that are used to treat patients with AML or MDS—this is specifically MDS, but it is still [a] myeloid malignancy in line with AML. The 2 common agents that are used to treat MDS include azacitidine and decitabine [among] a few others. Although they act similar, they’re metabolized in different ways, and mechanisms of resistance can develop with the MDS cell increasing metabolism of one agent or the other.

[The CASE4919] clinical trial focuses on cycling these 2 agents quickly every week—one dose for one agent earlier in the week and one dose for the other agent later in the week. The idea is that through the cycling, we prevent that metabolic escape and therefore [this] could result in better disease control for patients with MDS.

For AML, [the protocol in the SIERRA] trial, which is focusing on patients who have refractory AML, is trying to get them to curative therapy [with] allogeneic hematopoietic bone marrow transplant. [Those study results are] likely going to be published this year. This study involves using a radioisotope that will bind to acute leukemia cells as well as bone marrow cells. [In] giving that radioisotope combined with an antibody, you can ablate a patient’s bone marrow and potentially their leukemia with an infusion, and then rescue the patient with allogeneic transplant or bone marrow or blood making stem cells from a donor. The abstracts that have come out suggest a clear benefit to doing that process of [using] a radioisotope conditioning regimen followed by a transplant for patients with refractory leukemia other than the standard of care which is more chemotherapy. That could be practice changing in that setting.

What data was seen with inotuzumab ozogamicin in ALL?

The multi-institutional [CASE1916] clinical trial focuses on maintenance therapy after allogeneic transplant for ALL [with the] low-intensity therapy inotuzumab ozogamicin given once a month for 4 months after allogeneic transplant for patients with ALL. The idea is that it’s safe and effective.

We published phase 1 data on this [regimen in] patients with ALL at high risk for relapse. [Patients received] a transplant and then the 4 doses of maintenance inotuzumab ozogamicin, and we were able to show it is safe. In that phase 1 clinical trial the 1-year overall survival [rate] was 89%, which was quite good. Now inotuzumab ozogamicin is in a phase 2 clinical trial. Although it is not a randomized study, this could have implications for patients with ALL who are at high risk for relapse after allogeneic transplant.

What research is currently ongoing at Seidman in solid tumors?

Seidman does a lot of clinical trials, and we are able to manufacture our own CAR T-cell [therapies] and other cell therapy products. One of the interesting studies [we have is the phase 2 hSTAR GBM trial (NCT05052957)] in brain cancer, glioblastoma multiforme, which in general is uniformly fatal. We have developed a multi-step pathway and have a clinical trial for patients who have this disease. What the pathway looks like is when a patient is identified we allow them to get the surgery for removal of as much of the tumor as possible and then after they’ve recovered from the surgery, we collect a large amount of their blood making stem cells. We manufacture those blood making stem cells so that they become resistant to the chemotherapy that we traditionally give for patients with glioblastoma multiforme.

The reason why that’s important is the chemotherapy that we give for glioblastoma is often limited by dosing because of toxicity to the bone marrow so we can’t give larger doses [with] potentially more effectivity because it causes a lot of low blood counts. [After] the patient completes radiation to the site of the tumor, they undergo a transplant where they get the chemotherapy that’s effective against glioblastoma in high doses; they’re rescued with their genetically modified blood making stem cells that are now resistant to the next phase of their therapy for glioblastoma, which is usually the oral agent temozolomide. Once the patient’s blood counts recover, they start that maintenance therapy, and the idea is that we can increase that dose of temozolomide so much because there won’t be [as] much hematologic toxicity. We’re hoping we might be able to move the dial in terms of prolonging progression-free survival for these patients with this very complex but very innovative clinical trial.

References

1. 5-azacitidine and decitabine epigenetic therapy for myeloid malignancies. ClinicalTrials.gov. Updated March 12, 2024. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04187703
2. Inotuzumab ozogamicin post-transplant for acute lymphocytic leukemia. ClinicalTrials.gov. Updated February 29, 2024. Accessed May 1, 2024.https://classic.clinicaltrials.gov/ct2/show/NCT03104491
3. Study of Iomab-b vs. conventional care in older subjects with active, relapsed or refractory acute myeloid leukemia (SIERRA). ClinicalTrials.gov. Updated July 19, 2023. Accessed May 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT02665065
4. Boglarka G, Stuart S, Hannah C, et al. SIERRA trial results with a targeted radiotherapy, Iomab-B, a myeloablative conditioning with reduced intensity tolerability yields high CR, long terms survival in HSCT ineligible active r/r AML. Hemasphere. 2023;7(suppl 3):e2941723. doi:10.1097/01.HS9.0000967904.29417.23