Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia

Recruiting at 232 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: Hydroxyurea

Disqualifiers: Down syndrome, Charcot-Marie-Tooth, MYC translocation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

4997 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding a new drug, inotuzumab ozogamicin, to existing chemotherapy treatments can improve outcomes for those with High-Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). Inotuzumab ozogamicin is a targeted therapy that delivers chemotherapy directly to cancer cells. The trial also examines the effectiveness of standard chemotherapy for individuals with Mixed Phenotype Acute Leukemia (MPAL) and B-lymphoblastic lymphoma (B-LLy). It suits those newly diagnosed with B-ALL, MPAL, or B-LLy, who may have specific features like high white blood cell counts or leukemia in the central nervous system. Participants must not have received prior chemotherapy, except for steroids. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that, except for certain steroids, you should not have received any prior chemotherapy for your current diagnosis before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that inotuzumab ozogamicin caused some side effects in past studies. In trials with adults who have acute lymphoblastic leukemia, about half of the patients experienced low platelet counts, leading to bleeding, and low white blood cell counts, increasing the risk of infections. These side effects occurred in about 51% and 49% of patients, respectively.

While these side effects are important to consider, inotuzumab ozogamicin targets cancer cells specifically, limiting harm to healthy cells. This targeted approach generally results in fewer side effects compared to traditional chemotherapy. Despite the side effects, the FDA has approved this treatment for use in other conditions, indicating an acceptable level of safety. However, potential participants should understand these risks and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Inotuzumab Ozogamicin for treating Acute Lymphoblastic Leukemia (ALL) because it uses a novel approach by combining a monoclonal antibody with a chemotherapy agent. This treatment specifically targets leukemia cells by attaching to a protein called CD22, which is present on the surface of these cells, allowing for precise delivery of the chemotherapy agent directly into the cancerous cells. Unlike standard chemotherapy treatments, which can affect both healthy and cancerous cells, Inotuzumab Ozogamicin aims to minimize damage to healthy cells, potentially leading to fewer side effects and more effective treatment outcomes.

What evidence suggests that this trial's treatments could be effective for acute lymphoblastic leukemia?

Research has shown that inotuzumab ozogamicin, one of the treatments studied in this trial, effectively treats certain types of leukemia. In one study, 73% of patients responded well during the first cycle. This treatment targets cancer cells and delivers a potent chemotherapy drug directly to them. Real-world data indicates that patients with relapsed or hard-to-treat acute lymphoblastic leukemia experienced high remission rates, where cancer shrinks or disappears, and improved survival. These findings suggest that inotuzumab ozogamicin holds promising potential to enhance treatment outcomes for individuals with high-risk B-cell acute lymphoblastic leukemia. ^{4 5 6 7 8}

Who Is on the Research Team?

Jennifer L McNeer

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for patients under 25 years with high-risk B-cell Acute Lymphoblastic Leukemia, mixed phenotype acute leukemia, or B-lymphoblastic lymphoma. Eligible participants must meet specific white blood cell count criteria and be newly diagnosed based on bone marrow analysis or circulating leukemic cells. Exclusions include Down syndrome, prior significant treatment for leukemia, certain genetic conditions like Charcot-Marie-Tooth disease, pregnancy, breastfeeding women, and those not using effective contraception.

Inclusion Criteria

B-ALL and MPAL patients must be enrolled on APEC14B1 and consented to eligibility studies (Part A) prior to treatment and enrollment on AALL1732. Central confirmation of MPAL diagnosis must occur within 22 days of enrollment for suspected MPAL patients. Patients must be > 365 days and < 25 years of age. White blood cell count (WBC) criteria apply for patients with B-ALL and MPAL. Patient must have newly diagnosed B-ALL or MPAL with >= 25% blasts on a bone marrow aspirate or meet alternative diagnostic criteria. Patient must have newly diagnosed B-LLy Murphy stages III or IV, or stages I or II with steroid pretreatment. Central nervous system (CNS) status must be determined prior to enrollment. All patients and/or their parents or legal guardians must sign a written informed consent. All institutional, FDA, and NCI requirements for human studies must be met.

Exclusion Criteria

Patients with Down syndrome. Patients who have received prior cytotoxic chemotherapy for the current diagnosis. Patients who have received > 72 hours of hydroxyurea within one week prior to start of systemic protocol therapy. Patients with insufficient diagnostic bone marrow submitted for APEC14B1 testing. Patients with acute undifferentiated leukemia (AUL). Additional exclusion criteria for Murphy stage III/IV B-LLy patients or stage I/II patients with steroid pretreatment. Female patients who are pregnant or lactating. Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive initial chemotherapy including cytarabine, vincristine, daunorubicin, pegaspargase, and methotrexate to induce remission

5 weeks

Weekly visits for chemotherapy administration

Consolidation

Patients receive intensified chemotherapy to consolidate remission, including cyclophosphamide, cytarabine, mercaptopurine, and methotrexate

8 weeks

Bi-weekly visits for chemotherapy administration

Post-Consolidation Therapy

Patients receive further chemotherapy cycles including interim maintenance, delayed intensification, and maintenance phases

Up to 2 years

Regular visits every 3-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Follow-up visits every 3 months for 2 years, then every 4-6 months for the third year, and every 6-12 months for years 4-5

What Are the Treatments Tested in This Trial?

Interventions

• Calaspargase Pegol-mknl
• Cyclophosphamide
• Cytarabine
• Daunorubicin Hydrochloride
• Dexamethasone
• Doxorubicin Hydrochloride
• Inotuzumab Ozogamicin
• Mercaptopurine
• Methotrexate
• Pegaspargase
• Prednisolone
• Questionnaire Administration
• Thioguanine
• Vincristine Sulfate

Trial Overview The study tests if adding Inotuzumab Ozogamicin to post-induction chemotherapy improves outcomes in high-risk B-ALL patients. It also examines the effects of standard ALL therapy on MPAL and B-LLy without Inotuzumab. The trial includes various phases of chemotherapy with some patients randomly chosen to receive Inotuzumab Ozogamicin alongside other drugs like cyclophosphamide and methotrexate.

How Is the Trial Designed?

Group I: Arm IV (MPAL) Experimental Treatment 18 Interventions

See detailed description for Arm IV.

Group II: Arm III (HR B-ALL EXPERIMENTAL) Experimental Treatment 18 Interventions

See detailed description for Arm III.

Group III: Arm I (HR-FAV B-ALL) Experimental Treatment 17 Interventions

See detailed description for Arm I

Group IV: ARM V (B-LLY) Experimental Treatment 21 Interventions

See detailed description for Arm V.

Group V: Arm II (HR B-ALL CONTROL) Active Control 18 Interventions

See detailed description for Arm II.

Calaspargase Pegol-mknl is already approved in European Union, United States for the following indications:

Approved in European Union as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL)

Approved in United States as Besponsa for:

• Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A multicenter phase II clinical trial involving 39 adults aged 20-60 with acute lymphoblastic leukemia (ALL) showed that a pediatric-inspired chemotherapy regimen using pegaspargase resulted in a high complete response rate of 97%.

While the treatment was associated with significant toxicities, such as grade 3-4 hyperbilirubinemia and hypertriglyceridemia, these were manageable, and the overall survival rate at 3 years was 76.4%, indicating that pegaspargase can be safely integrated into intensive chemotherapy for adults with ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Geyer, MB., Ritchie, EK., Rao, AV., et al.[2021]

Inotuzumab ozogamicin is an effective treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), as demonstrated in the phase III INO-VATE trial, which led to its approval for this high-risk group.

This antibody-drug conjugate works by targeting CD22 on tumor cells, leading to cell death, and ongoing trials are exploring its use in combination with low-dose chemotherapy and in earlier treatment stages to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin for the treatment of patients with acute lymphocytic leukemia. Choudhry, A., O'Brien, SM.[2019]

In a study of 15 infants and young children with relapsed or refractory acute lymphoblastic leukaemia (ALL), treatment with inotuzumab ozogamicin (InO) resulted in a 47% complete remission rate, indicating its potential efficacy in this challenging population.

The six-month overall survival rate was 47%, but there were safety concerns, as two patients developed veno-occlusive disease after undergoing a transplant, highlighting the need for careful monitoring and further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series. Brivio, E., Chantrain, CF., Gruber, TA., et al.[2021]

Inotuzumab ozogamicin (InO) demonstrated significant antitumor activity in patients with CD22-positive relapsed/refractory acute lymphoblastic leukemia, with 68% of patients achieving complete remission or complete remission with incomplete marrow recovery, and 84% achieving minimal residual disease negativity.

The recommended phase 2 dose of InO was confirmed at 1.8 mg/m2 per cycle, and while treatment-related toxicities were primarily cytopenias, the drug was generally well tolerated, indicating a favorable safety profile alongside its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. DeAngelo, DJ., Stock, W., Stein, AS., et al.[2019]

In a study involving 5,377 children with standard-risk B-acute lymphoblastic leukemia (ALL), the 6-year continuous complete remission (CCR) rate for low-risk patients was 94.7%, indicating high efficacy of the treatment.

Adding intensified pegaspargase doses did not significantly improve CCR or overall survival rates compared to standard therapy, suggesting that the standard treatment is effective and can be administered with limited toxicity as an outpatient procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331. Mattano, LA., Devidas, M., Maloney, KW., et al.[2022]

Inotuzumab ozogamicin is an effective treatment for adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL), approved by the EMA in June 2017, and works by delivering a cytotoxic agent directly into cancer cells, leading to their death.

The drug is specifically indicated for patients who have not responded to at least one tyrosine kinase inhibitor, and ongoing trials are exploring its use in combination with chemotherapy for newly diagnosed B-cell ALL and in other types of leukaemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin: First Global Approval. Lamb, YN.[2019]

Inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate, has been approved for treating adults with relapsed or refractory acute lymphoblastic leukemia (ALL) and shows improved response rates and survival compared to standard chemotherapy.

This treatment not only enhances the chances of achieving minimal residual disease negativity but also increases the likelihood of patients being eligible for allogeneic stem cell transplants, which can be crucial for their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. Williams, S., Kim, M.[2020]

Inotuzumab Ozogamicin (INO) significantly reduces hospitalization days for patients with relapsed/refractory acute lymphoblastic leukemia (ALL), averaging 7.6 days per patient month compared to 18.4 days for standard chemotherapy, indicating a lower healthcare burden.

The treatment with INO not only improves overall survival and remission rates but also leads to fewer hospitalizations due to treatment-related complications, suggesting it may be a more cost-effective option for managing R/R ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Burden of hospitalization in acute lymphoblastic leukemia patients treated with Inotuzumab Ozogamicin versus standard chemotherapy treatment. Marks, DI., van Oostrum, I., Mueller, S., et al.[2021]

Inotuzumab ozogamicin, a targeted therapy for relapsed/refractory acute lymphoblastic leukemia, effectively binds to CD22, which is present in 90-100% of malignant B-lymphocytes, showing promise for patients who have undergone extensive prior treatments.

The therapy is generally well-tolerated, although there is a risk of veno-occlusive disease, making it a potentially beneficial option for patients seeking allogeneic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of inotuzumab ozogamicin in the treatment of relapsed/refractory acute lymphoblastic leukemia. George, B., Kantarjian, H., Jabbour, E., et al.[2019]

Pegaspargase is a crucial chemotherapy drug for treating acute lymphoblastic leukemia (ALL) in both children and adults, derived from E. coli, which requires careful management due to its specific toxicity profile.

The review highlights the importance of understanding and managing the common toxicities associated with Pegaspargase treatment to enhance safety, tolerability, and ultimately improve survival outcomes for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prevention and management of pegaspargase associated-toxicities (excluding coagulation abnormalities). Recommendations of the French Society of Children and Adolescent Cancers (Leukemia committee)]. Poirée, M., Neumann, F., Thomas, C., et al.[2023]

Inotuzumab ozogamicin (InO) demonstrated superior clinical activity compared to standard-of-care treatments in patients with relapsed/refractory B-cell acute lymphoblastic leukemia, as shown in the phase 3 INO-VATE trial.

Patients receiving InO reported significantly better quality of life and functioning scores compared to those on standard-of-care, indicating a favorable benefit/risk ratio for InO in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes from a phase 3 randomized controlled trial of inotuzumab ozogamicin versus standard therapy for relapsed/refractory acute lymphoblastic leukemia. Kantarjian, HM., Su, Y., Jabbour, EJ., et al.[2019]

In a study involving 239 patients aged 1 to 21 with newly diagnosed acute lymphoblastic leukemia (ALL), calaspargase pegol demonstrated similar efficacy to the standard pegaspargase, achieving comparable rates of complete remission (99% for pegaspargase vs. 95% for calaspargase).

Calaspargase, administered every 3 weeks, showed a significantly higher serum asparaginase activity at day 25 compared to pegaspargase (88% vs. 17% with therapeutic levels), while both treatments had similar toxicity profiles and 5-year event-free survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. Vrooman, LM., Blonquist, TM., Stevenson, KE., et al.[2021]

Pegaspargase (Oncaspar) was approved for first-line treatment of acute lymphoblastic leukemia (ALL) in children, showing similar efficacy to native L-asparaginase (Elspar) in depleting serum and cerebrospinal fluid asparagine levels during a clinical trial with 118 participants aged 1-9 years.

While both treatments had comparable event-free survival rates of around 80% at 3 years, pegaspargase was associated with serious toxicities such as anaphylaxis and thrombosis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Dinndorf, PA., Gootenberg, J., Cohen, MH., et al.[2022]

Inotuzumab Ozogamicin (InO) demonstrated a high overall response rate of 81.5% in children and adolescents with relapsed or refractory B cell acute lymphoblastic leukemia, meeting the study's primary endpoint.

The main safety concern identified was sinusoidal obstructive syndrome (SOS), which occurred in seven patients, especially when InO was followed by hematopoietic stem cell transplantation (HSCT).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial. Pennesi, E., Michels, N., Brivio, E., et al.[2023]

Citations

1. besponsa.pfizerpro.com besponsa.pfizerpro.com/efficacy/adult-clinical-data%E2%80%94ino-vate

BESPONSA® (inotuzumab ozogamicin) CR/CRi | Safety Info In the remission analysis population of 109 patients randomized to receive BESPONSA, 73% (n=64/88) responded in Cycle 1 and 24% (n=21/88) responded in Cycle 2.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12427359/

Real‐World Data on Inotuzumab Ozogamicin for Adult ... InO demonstrated high remission and MRD negativity rates in Chilean patients with R/R ALL, with OS and PFS comparable to existing research.

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1422/531484/Safety-and-Efficacy-Results-of-Dose-Adjusted

Safety and Efficacy Results of Dose-Adjusted Inotuzumab ... Conclusions: The results of this study indicate that dose-adjusted InO is a well-tolerated and effective treatment option for B-ALL adults with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12533514/

Inotuzumab ozogamicin in adult acute lymphoblastic leukemia Outcomes have been historically poor in adults with relapsed/refractory (R/R) B-cell ALL, with a 5-year overall survival (OS) rate of <10% with ...

5. haematologica.org haematologica.org/article/view/11921

Efficacy and safety of currently approved and lower starting ... This study evaluated efficacy and safety of the currently approved InO starting dose and a lower dose in adults with R/R ALL who were eligible for HSCT.

6. besponsa.pfizerpro.com besponsa.pfizerpro.com/safety/adult-safety-data

BESPONSA® (inotuzumab ozogamicin) Safety Information In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively.

7. pfe-pfizercom-prod.s3.amazonaws.com pfe-pfizercom-prod.s3.amazonaws.com/products/material_safety_data/BESPONSA_Inotuzumab_ozogamicin_20-march-2019.pdf

SAFETY DATA SHEET Precautionary Statements: P201 - Obtain special instructions before use. P260 - Do not breathe dust/fume/gas/mist/vapors/spray.

8. ema.europa.eu ema.europa.eu/en/documents/product-information/besponsa-epar-product-information_en.pdf

Besponsa, INN-inotuzumab ozogamicin Adverse reactions included treatment-emergent, all-causality events that commenced on, or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, ...