Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia

Recruiting at 214 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

Trial Summary

What is the purpose of this trial?

This phase III trial studies whether inotuzumab ozogamicin added to post-induction chemotherapy for patients with High-Risk B-cell Acute Lymphoblastic Leukemia (B-ALL) improves outcomes. This trial also studies the outcomes of patients with mixed phenotype acute leukemia (MPAL), and B-lymphoblastic lymphoma (B-LLy) when treated with ALL therapy without inotuzumab ozogamicin. Inotuzumab ozogamicin is a monoclonal antibody, called inotuzumab, linked to a type of chemotherapy called calicheamicin. Inotuzumab attaches to cancer cells in a targeted way and delivers calicheamicin to kill them. Other drugs used in the chemotherapy regimen, such as cyclophosphamide, cytarabine, dexamethasone, doxorubicin, daunorubicin, methotrexate, leucovorin, mercaptopurine, prednisone, thioguanine, vincristine, and pegaspargase or calaspargase pegol work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial will also study the outcomes of patients with mixed phenotype acute leukemia (MPAL) and disseminated B lymphoblastic lymphoma (B-LLy) when treated with high-risk ALL chemotherapy. The overall goal of this study is to understand if adding inotuzumab ozogamicin to standard of care chemotherapy maintains or improves outcomes in High Risk B-cell Acute Lymphoblastic Leukemia (HR B-ALL). The first part of the study includes the first two phases of therapy: Induction and Consolidation. This part will collect information on the leukemia, as well as the effects of the initial treatment, to classify patients into post-consolidation treatment groups. On the second part of this study, patients with HR B-ALL will receive the remainder of the chemotherapy cycles (interim maintenance I, delayed intensification, interim maintenance II, maintenance), with some patients randomized to receive inotuzumab. The patients that receive inotuzumab will not receive part of delayed intensification. Other aims of this study include investigating whether treating both males and females with the same duration of chemotherapy maintains outcomes for males who have previously been treated for an additional year compared to girls, as well as to evaluate the best ways to help patients adhere to oral chemotherapy regimens. Finally, this study will be the first to track the outcomes of subjects with disseminated B-cell Lymphoblastic Leukemia (B-LLy) or Mixed Phenotype Acute Leukemia (MPAL) when treated with B-ALL chemotherapy.

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.

What data supports the effectiveness of the drug Inotuzumab Ozogamicin for treating acute lymphoblastic leukemia?

Inotuzumab Ozogamicin has shown to improve response rates, achieve minimal residual disease negativity, and increase survival compared to standard chemotherapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. It also offers more opportunities for patients to proceed to stem cell transplants. ^{1 2 3 4 5}

Is Inotuzumab Ozogamicin safe for humans?

The safety data for pegaspargase, a related treatment used in acute lymphoblastic leukemia, shows that it can cause serious side effects like allergic reactions, pancreatitis (inflammation of the pancreas), and blood clotting issues. However, these side effects are manageable, and the treatment is generally considered safe when used as part of a multi-drug regimen. ^{6 7 8 9 10}

What makes the drug Inotuzumab Ozogamicin unique for treating acute lymphoblastic leukemia?

Inotuzumab Ozogamicin is unique because it targets CD22, a protein found on most B-cell leukemia cells, and delivers a powerful toxin directly to these cells, causing them to die. This approach is different from standard chemotherapy and has shown promise in patients who have not responded to other treatments, offering a new option for those with relapsed or refractory acute lymphoblastic leukemia. ^{1 11 12 13 14}

Research Team

Jennifer L McNeer

Principal Investigator

Children's Oncology Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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 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) 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 (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 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]

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]

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]

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]

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, 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]

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 (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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin in Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia. [2020]

2. United States 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. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Burden of hospitalization in acute lymphoblastic leukemia patients treated with Inotuzumab Ozogamicin versus standard chemotherapy treatment. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. [2021]

7. United States 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. [2022]

8. France 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)]. [2023]

9. Italy 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. [2021]

10. England pubmed.ncbi.nlm.nih.gov

FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). [2022]

11. England pubmed.ncbi.nlm.nih.gov

Role of inotuzumab ozogamicin in the treatment of relapsed/refractory acute lymphoblastic leukemia. [2019]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Inotuzumab Ozogamicin: First Global Approval. [2019]

13. England 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. [2023]

14. Spain pubmed.ncbi.nlm.nih.gov

Inotuzumab ozogamicin for the treatment of patients with acute lymphocytic leukemia. [2019]