Lorlatinib + Standard Therapy for Neuroblastoma

Recruiting at 170 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Disqualifiers: Pregnancy, Bone marrow failure, 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: 3

724 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Iobenguane I-131, Lorlatinib, Lorbrena for neuroblastoma?

Research shows that Iobenguane I-131 (a radioactive drug) is considered safe and potentially effective for treating high-risk neuroblastoma, especially in cases where the cancer has returned or is resistant to other treatments. ^{1 2 3 4 5}

Is the combination of Lorlatinib and Iobenguane I-131 safe for treating neuroblastoma?

Lorlatinib has been studied for safety in children and adults with neuroblastoma, showing common side effects like high triglycerides, high cholesterol, and weight gain, with some neurobehavioral effects in adults that improved with dose adjustments. Iobenguane I-131 is considered a safe treatment for neuroblastoma, used in various studies for high-risk cases. ^{1 2 6 7 8}

How does the drug lorlatinib differ from other treatments for neuroblastoma?

Lorlatinib is unique because it is a third-generation ALK inhibitor specifically effective against ALK-driven neuroblastoma that is resistant to other treatments like crizotinib. It can be used alone or in combination with chemotherapy, showing promising response rates in both children and adults with relapsed or refractory neuroblastoma. ^{4 6 7 9 10}

What is the purpose of this trial?

This phase III trial studies iobenguane I-131 or lorlatinib and standard therapy in treating younger patients with newly-diagnosed high-risk neuroblastoma or ganglioneuroblastoma. Radioactive drugs, such as iobenguane I-131, may carry radiation directly to tumor cells and not harm normal cells. Lorlatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving iobenguane I-131 or lorlatinib and standard therapy may work better compared to lorlatinib and standard therapy alone in treating younger patients with neuroblastoma or ganglioneuroblastoma.

Research Team

Steven DuBois

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for young patients up to 30 years old with high-risk neuroblastoma or ganglioneuroblastoma. They must have certain levels of kidney and liver function, no prior systemic therapy (with some exceptions), and can't be pregnant or breastfeeding. Patients need a confirmed diagnosis and meet specific criteria based on their disease stage and features.

Inclusion Criteria

My cancer is in an advanced stage with a specific genetic change.

I was diagnosed with a certain stage of cancer before it spread, and I haven't had chemotherapy.

I am a child aged 10 to less than 13 years with a specific health measure.

Exclusion Criteria

I have a condition where my bone marrow doesn't produce enough blood cells.

I cannot receive targeted radiopharmaceutical therapy due to my health conditions.

Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive cyclophosphamide, topotecan hydrochloride, and other chemotherapy agents as part of induction therapy

5 cycles (approximately 15 weeks)

Multiple visits for chemotherapy administration

Consolidation Therapy

Patients undergo high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT)

2 cycles (approximately 8 weeks)

Inpatient stay for HSCT

Post-Consolidation Therapy

Patients receive sargramostim, dinutuximab, isotretinoin, and possibly lorlatinib

6 cycles (approximately 6 months)

Regular visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 60 months

Every 3 months for 18 months, then every 6 months

Treatment Details

Interventions

• Iobenguane I-131
• Lorlatinib

Trial Overview The study tests adding iobenguane I-131 or lorlatinib to standard therapy in treating high-risk neuroblastoma. Iobenguane I-131 delivers radiation directly to cancer cells, while lorlatinib blocks enzymes that help tumor growth. The goal is to see if these additions improve treatment outcomes.

Participant Groups

Group I: Arm E (lorlatinib, chemotherapy, HSCT, EBRT) Experimental Treatment 22 Interventions

See Arm E in detailed description.

Group II: Arm D (chemotherapy, HSCT, EBRT) Experimental Treatment 22 Interventions

See Arm D in detailed description.

Group III: Arm C (Iobenguane I-131, chemotherapy, BuMel, HSCT, EBRT) Experimental Treatment 24 Interventions

See Arm C in detailed description. Closed to accrual as of 12/17/20.

Group IV: Arm B (Iobenguane I-131, chemotherapy, HSCT, EBRT) Experimental Treatment 24 Interventions

See Arm B in detailed description.

Group V: Arm A (chemotherapy, HSCT, EBRT) Experimental Treatment 22 Interventions

See Arm A in detailed description.

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

In a pilot study involving 68 children with newly diagnosed high-risk neuroblastoma, 86.8% completed induction chemotherapy and received 131 I-MIBG therapy, demonstrating the treatment's feasibility.

The study found that while there were some severe side effects, including sinusoidal obstruction syndrome (SOS), the 15 mCi/kg dose of 131 I-MIBG showed a high feasibility rate of 96.7%, supporting further investigation in a larger randomized trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study. Weiss, BD., Yanik, G., Naranjo, A., et al.[2022]

A phase 1 study demonstrated that lorlatinib is both safe and effective for children with treatment-refractory or relapsed ALK-driven neuroblastoma, highlighting its potential as a new treatment option.

These preliminary findings suggest that lorlatinib could provide hope for young patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. Suk, Y., Singh, SK.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Iodine-131-meta-iodobenzylguanidine therapy for patients with newly diagnosed high-risk neuroblastoma. [2020]

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

131 I-Meta-iodobenzylguanidine followed by busulfan and melphalan and autologous stem cell rescue in high-risk neuroblastoma. [2021]

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

Anatomic patterns of relapse and progression following treatment with 131 I-MIBG in relapsed or refractory neuroblastoma. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma. [2020]

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

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study. [2022]

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

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. [2023]

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

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. [2023]

8. Italy pubmed.ncbi.nlm.nih.gov

Treatment of neuroblastoma with [131I]metaiodobenzylguanidine: long-term results in 25 patients. [2013]

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

Tandem stem cell rescue as consolidation therapy for high-risk neuroblastoma. [2012]

10. Ireland pubmed.ncbi.nlm.nih.gov

Small molecule inhibitor agerafenib effectively suppresses neuroblastoma tumor growth in mouse models via inhibiting ERK MAPK signaling. [2020]