What side effects are associated with this type of intervention?

Topoisomerase I inhibitors, such as irinotecan (VAL-413), commonly cause side effects including diarrhea, nausea, vomiting, and myelosuppression, which can lead to decreased blood cell counts and increased risk of infection. Temozolomide, an alkylating agent, is associated with side effects such as nausea, vomiting, fatigue, constipation, and myelosuppression. Both drugs can also cause liver enzyme abnormalities and, less commonly, severe allergic reactions. These side effects necessitate careful monitoring and supportive care during treatment.

What prior FDA approvals exist?

The FDA has approved several treatments for Neuroblastoma, including Topoisomerase I Inhibitors and Alkylating Agents. Irinotecan, a Topoisomerase I Inhibitor, has been used in combination with other drugs for treating recurrent Neuroblastoma. Temozolomide, an Alkylating Agent, has also been utilized in various treatment regimens for Neuroblastoma. These drugs work by interfering with DNA replication and repair, leading to cancer cell death. The combination of these agents, as studied in the VAL-413 (Orotecan®) and Temozolomide trial, aims to enhance treatment efficacy for recurrent pediatric solid tumors, including Neuroblastoma.

What other types of research exist?

Promising novel alternatives for Neuroblastoma treatment in 2024 include: 1) GD2-targeted immunotherapies such as Dinutuximab, which has shown efficacy in high-risk neuroblastoma. 2) ALK inhibitors like Lorlatinib for patients with ALK mutations. 3) Anti-GD2 CAR T-cell therapies, which are being actively investigated in clinical trials. 4) MIBG (metaiodobenzylguanidine) therapy, particularly in combination with other agents. These therapies represent advancements in targeted and immunotherapy approaches for neuroblastoma.

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Alkylating agents

Oral Irinotecan + Temozolomide for Pediatric Solid Cancers

Phase 1

Recruiting

Led By Kyle Jackson, M.D.

Research Sponsored by Valent Technologies, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, as described below: Myelosuppressive chemotherapy: patients must not have received myelosuppressive chemotherapy within 21 days of first study treatment, but nitrosourea within 8 weeks (42 days) of first study treatment Anti-cancer agents not known to be myelosuppressive (e.g., not associated with drops in platelet or neutrophil count): must not have received these therapies within 7 days of first study treatment, or at least 5 half-lives of the agent (whichever is longer) Antibody therapy: At least 4 weeks must have elapsed since last antibody dose prior to first study treatment Radiation therapy: At least two weeks must have elapsed since last local palliative radiation (small port) prior to first study treatment. At least 6 weeks must have elapsed if more substantial radiation was administered (e.g., >50% pelvis, craniospinal, whole body), or therapeutic radiolabeled 131I MIBG or other radiopharmaceutical therapy. High-Dose Chemotherapy with Autologous Stem Cell Transplant/Rescue: At least two months must have elapsed since receiving autologous hematopoietic stem cells prior to first study treatment. Patients who have had allogeneic transplants are ineligible. Hematopoietic growth factors: must not have been received in the 14 days prior to first study treatment for a long-acting growth factor (e.g., pegfilgrastim), or 7 days prior to first study treatment for short-acting growth factor.

Karnofsky Performance Status ≥ 50% for patients > 16 years of age and Lansky Performance Status ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Must not have

Patients taking strong inducers of CYP3A4, including but not limited to phenobarbital, phenytoin, carbamazepine, oxcarbazepine (Trileptal), rifampin, voriconazole, itraconazole, ketoconazole or other systemically-administered azole antifungal drugs, aprepitant (Emend) or St. John's Wort, in the 2 weeks prior to first study treatment are ineligible

Patients who have uncontrolled infections, require IV antibiotics at time of enrollment, or who are currently receiving treatment for Clostridium difficile infection are excluded

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 17 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new flavored oral medicine called Orotecan® combined with temozolomide to treat children and young adults with recurring solid tumors. The treatment works by damaging the DNA of cancer cells to stop their growth. Temozolomide has been used in various trials for treating different types of tumors, including gliomas and medulloblastomas.

Who is the study for?

This trial is for children and young adults aged 1 to 30 with recurrent solid tumors like neuroblastoma or Ewing sarcoma. They must have a certain level of physical ability, no uncontrolled infections, not be pregnant, and agree to use contraception. Participants need normal organ function and can't join if they've had severe allergic reactions to specific drugs or are on certain medications.

What is being tested?

The study tests the safety and effectiveness of a flavored oral form of Irinotecan (VAL-413) combined with Temozolomide in treating pediatric solid tumors. It's designed to see how well patients tolerate this new formulation and measure its impact on their cancer.

What are the potential side effects?

Possible side effects include digestive issues such as diarrhea, nausea, vomiting; lowered blood counts leading to increased infection risk; fatigue; liver problems indicated by altered blood tests; hair loss; and potential allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am over 16 and can do most activities, or if under 16, I can do many activities without help.

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My kidney function is within the required range for my age and gender.

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I am between 1 and 30 years old.

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My cancer was confirmed by a tissue test at diagnosis or relapse.

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My liver enzyme ALT levels are within 5 times the normal limit.

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My kidney function is within the normal range.

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My cancer was confirmed by a tissue test at diagnosis or relapse.

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My bilirubin levels are within the normal range for my age.

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I haven't taken any cancer drugs that lower blood counts in the last 7 days or 5 half-lives.

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I am between 1 and 30 years old.

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It has been over 4 weeks since my last antibody therapy dose.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have not taken strong medication inducers like phenobarbital or St. John's Wort in the last 2 weeks.

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I do not have an uncontrolled infection or need IV antibiotics.

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I have never had a severe allergic reaction to dacarbazine or certain antibiotics.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 17 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~17 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 17 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Recommended Phase II Dose (RP2D)

Secondary study objectives

AUCinf

AUClast

Adverse Events

+9 more

Side effects data

From 2016 Phase 2 trial • 175 Patients • NCT01055314

36%

Febrile neutropenia

31%

Death NOS

30%

Diarrhea

22%

Pain

21%

Hyperglycemia

16%

Anorexia

16%

Infections and infestations - Other, specify

16%

Alanine aminotransferase increased

14%

Hypokalemia

13%

Nausea

11%

Hyponatremia

10%

Weight loss

Aspartate aminotransferase increased

Mucositis oral

Anemia

Vomiting

Constipation

Dehydration

Hypophosphatemia

Platelet count decreased

Sepsis

Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify

Catheter related infection

Colitis

Abdominal pain

Hypotension

White blood cell decreased

GGT increased

Hypocalcemia

Urinary retention

Hypoalbuminemia

Fever

Typhlitis

Anxiety

Neutrophil count decreased

Urinary tract infection

Peripheral motor neuropathy

Enterocolitis

Lipase increased

Pleural effusion

Serum amylase increased

Skin infection

Epistaxis

Urinary tract obstruction

Blood bilirubin increased

Lymphocyte count decreased

Syncope

Wound infection

Dermatitis radiation

Hypertension

Sinus tachycardia

Edema limbs

Bone pain

Dyspnea

Hematuria

Hypercalcemia

Vulval infection

Upper gastrointestinal hemorrhage

Thromboembolic event

Depressed level of consciousness

Stridor

Allergic reaction

Back pain

Lung infection

Urticaria

Acute kidney injury

Muscle weakness lower limb

Musculoskeletal and connective tissue disorder - Other, specify

Pain in extremity

Peripheral sensory neuropathy

Proctitis

Skin ulceration

Apnea

Stoma site infection

Tumor pain

Left ventricular systolic dysfunction

Pancreatitis

Portal hypertension

Rectal hemorrhage

Creatinine increased

Enterocolitis infectious

Hyperkalemia

Investigations - Other, specify

Abdominal distension

Heart failure

Ascites

Vascular disorders - Other, specify

Anal hemorrhage

Penile pain

Bone marrow hypocellular

Vasovagal reaction

Gastrointestinal disorders - Other, specify

Soft tissue infection

Delirium

Tracheitis

Seizure

Hepatobiliary disorders - Other, specify

Esophageal pain

Anal mucositis

Menorrhagia

Sore throat

Anaphylaxis

Fracture

Hydrocephalus

Device related infection

Tooth infection

Gastric ulcer

Sinusitis

Skin and subcutaneous tissue disorders - Other, specify

Pharyngitis

Pyramidal tract syndrome

Anal ulcer

Depression

Ejection fraction decreased

Rash maculo-papular

Pruritus

Myositis

Nail infection

Pain of skin

Pleuritic pain

Pneumonitis

Pneumothorax

Postoperative hemorrhage

Renal and urinary disorders - Other, specify

Respiratory, thoracic and mediastinal disorders - Other, specify

Salivary duct inflammation

Small intestine infection

Alkaline phosphatase increased

Appendicitis

Spinal fracture

Disseminated intravascular coagulation

Ear and labyrinth disorders - Other, specify

Endocrine disorders - Other, specify

Esophageal stenosis

Esophagitis

Gastric hemorrhage

Gum infection

Tumor lysis syndrome

Upper respiratory infection

Hypertriglyceridemia

Hypoxia

Ileus

INR increased

Laryngeal edema

Multi-organ failure

Myelodysplastic syndrome

Oral hemorrhage

Oral pain

Pulmonary edema

Rectal fistula

Rectal pain

Respiratory failure

Bladder spasm

Chest wall pain

Confusion

Congenital, familial and genetic disorders - Other, specify

CPK increased

Dizziness

Encephalopathy

Eye disorders - Other, specify

Generalized muscle weakness

Hoarseness

Hypernatremia

Hypoglycemia

Hypomagnesemia

Insomnia

Irregular menstruation

Irritability

Joint range of motion decreased cervical spine

Kyphosis

Lethargy

Headache

Laryngeal mucositis

Pelvic pain

Esophageal infection

Abdominal infection

Acidosis

Anal fistula

Fall

Fatigue

Gait disturbance

100%

80%

60%

40%

20%

Study treatment Arm

Group 1 (Chemotherapy, Radiation Therapy, Cixutumumab)

Group 2 (Chemotherapy, Radiation Therapy, Temozolomide)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: 90 mg/m2/day VAL-413 (Orotecan®)Experimental Treatment2 Interventions

Orotecan® at 90 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Group II: 75 mg/m2/day VAL-413 (Orotecan®)Experimental Treatment2 Interventions

In the event the 90 mg/m2/day starting dose is not tolerable due to toxicity, a lower starting dose of 75 mg/m2/day may be implemented. Orotecan® at 75 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Group III: 110 mg/m2/day VAL-413 (Orotecan®)Experimental Treatment2 Interventions

Orotecan® at 110 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Temozolomide

2010

Completed Phase 3

~1880

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Irinotecan, a topoisomerase I inhibitor, works by preventing the relaxation of DNA supercoiling, which is necessary for DNA replication and transcription. This leads to DNA damage and cell death, particularly in rapidly dividing cancer cells like those in neuroblastoma. Temozolomide, an alkylating agent, adds alkyl groups to DNA, causing DNA cross-linking and strand breaks, which also result in cell death. These mechanisms are crucial for neuroblastoma patients because they target the cancer cells' ability to proliferate, thereby reducing tumor growth and potentially improving patient outcomes.

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26.