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Pevonedistat, Irinotecan, and Temozolomide in Treating Patients With Recurrent or Refractory Solid Tumors or Lymphoma
Phase 1 trial testing Irinotecan in Recurrent Lymphoma in 30 participants. Completed in 30 September 2024.
| Lead sponsor | Children's Oncology Group |
|---|---|
| Phase | Phase 1 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | na |
| Design | single group |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 30 |
| Start date | 11 January 2018 |
| Primary completion | 30 September 2021 |
| Estimated completion | 30 September 2024 |
| Sites | 20 locations across United States |
Children's Oncology Group — full company profile →
Adults 6 Months to 21, any sex, with Recurrent Lymphoma or Recurrent Malignant Solid Neoplasm. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) will be the maximum dose at which fewer than one-third of patients experience dose limiting toxicities.
| Group | Value | 95% CI |
|---|---|---|
| Treatment (Pevonedistat, Temozolomide, Irinotecan) | 35 |
Frequency of patients who experience at least one grade 3 or higher toxicity that is at least possibly attributable to pevonedistat using the Common Terminology Criteria for Adverse Events version 5.0 by dose level stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 5 | |
| Part A Dose Level 2: 20 mg/m^2 | 4 | |
| Part A Dose Level 3: 25 mg/m^2 | 6 | |
| Part A Dose Level 4: 35 mg/m^2 | 2 | |
| Part A PK Dose Level 4: 35 mg/m^2 | 4 |
Median (Range) for the time required for the serum concentration to fall to 50% of its starting dose by dose level stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 5.3 | 4.7 – 7.4 |
| Part A Dose Level 2: 20 mg/m^2 | 5 | 4.1 – 6.0 |
| Part A Dose Level 3: 25 mg/m^2 | 5.2 | 4.0 – 5.5 |
| Part A Dose Level 4: 35 mg/m^2 | 4.7 | 4.0 – 6.7 |
| Part A PK Dose Level 4: 35 mg/m^2 | 6.1 | 3.9 – 7.9 |
Median (Range) for the time at which the maximum (peak) serum concentration occurs by dose level stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 1. | 1.0 – 1.6 |
| Part A Dose Level 2: 20 mg/m^2 | 1 | 1.0 – 2.5 |
| Part A Dose Level 3: 25 mg/m^2 | 1 | 0.9 – 1.4 |
| Part A Dose Level 4: 35 mg/m^2 | 1.1 | 1.0 – 1.1 |
| Part A PK Dose Level 4: 35 mg/m^2 | 1.1 | 1.0 – 1.5 |
Median (Range) for the maximum (peak) serum concentration by dose level stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 156 | 87.9 – 208.0 |
| Part A Dose Level 2: 20 mg/m^2 | 218.5 | 170.5 – 335.0 |
| Part A Dose Level 3: 25 mg/m^2 | 303.5 | 174.0 – 365.5 |
| Part A Dose Level 4: 35 mg/m^2 | 419 | 238.0 – 689.0 |
| Part A PK Dose Level 4: 35 mg/m^2 | 363.8 | 214.0 – 2367.0 |
Median (range) of the area under the drug concentration over time (pre-dose and then 0, 1, 2, 4, 6-8, and 24-hours post-dose infusion) curve stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 803 | 608.0 – 1010.0 |
| Part A Dose Level 2: 20 mg/m^2 | 973.5 | 865.0 – 1928.0 |
| Part A Dose Level 3: 25 mg/m^2 | 1340 | 990.0 – 1890.0 |
| Part A Dose Level 4: 35 mg/m^2 | 2018.5 | 1505.0 – 2535.0 |
| Part A PK Dose Level 4: 35 mg/m^2 | 1957 | 1583.0 – 5733.0 |
Median (Range) for the rate of elimination of the drug by dose level stratified by study part and dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 18.8 | 14.8 – 24.7 |
| Part A Dose Level 2: 20 mg/m^2 | 20.8 | 10.6 – 23.3 |
| Part A Dose Level 3: 25 mg/m^2 | 18.9 | 13.2 – 25.4 |
| Part A Dose Level 4: 35 mg/m^2 | 17.5 | 13.8 – 23.3 |
| Part A PK Dose Level 4: 35 mg/m^2 | 17.9 | 10.2 – 22.1 |
Frequency of disease response (best overall response of partial or complete response) assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR by dose level.
| Group | Value | 95% CI |
|---|---|---|
| Part A Dose Level 1: 15 mg/m^2 | 1 | |
| Part A Dose Level 2: 20 mg/m^2 | 1 | |
| Part A Dose Level 3: 25 mg/m^2 | 0 | |
| Part A Dose Level 4: 35 mg/m^2 | 0 | |
| Part A PK Dose Level 4: 35 mg/m^2 | 0 |
Time frame: Up to 4 years. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Part A Dose Level 1: 15 mg… | Part A Dose Level 2: 20 mg… | Part A Dose Level 3: 25 mg… | Part A Dose Level 4: 35 mg… | Part A PK Dose Level 4: 35… |
|---|---|---|---|---|---|---|
| Lymphocyte count decreased | Investigations | — | — | — | — | — |
| White blood cell decreased | Investigations | — | — | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — | — | — |
| Hyperglycemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypokalemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — | — | — |
| Anemia | Blood and lymphatic system disorders | — | — | — | — | — |
| Anorexia | Metabolism and nutrition disorders | — | — | — | — | — |
| Aspartate aminotransferase increased | Investigations | — | — | — | — | — |
| Ataxia | Nervous system disorders | — | — | — | — | — |
| Blood bilirubin increased | Investigations | — | — | — | — | — |
| Bone marrow hypocellular | Blood and lymphatic system disorders | — | — | — | — | — |
| Bone pain | Musculoskeletal and connective tissue disorders | — | — | — | — | — |
| Diarrhea | Gastrointestinal disorders | — | — | — | — | — |
| Fever | General disorders | — | — | — | — | — |
| Flu like symptoms | General disorders | — | — | — | — | — |
| Glucose intolerance | Metabolism and nutrition disorders | — | — | — | — | — |
| Hearing impaired | Ear and labyrinth disorders | — | — | — | — | — |
| Hypercalcemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hyperkalemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypotension | Vascular disorders | — | — | — | — | — |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — |
| Ileal obstruction | Gastrointestinal disorders | — | — | — | — | — |
| Lung infection | Infections and infestations | — | — | — | — | — |
| Reaction | System | Part A Dose Level 1: 15 mg… | Part A Dose Level 2: 20 mg… | Part A Dose Level 3: 25 mg… | Part A Dose Level 4: 35 mg… | Part A PK Dose Level 4: 35… |
|---|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | — | — | — | — | — |
| Aspartate aminotransferase increased | Investigations | — | — | — | — | — |
| Diarrhea | Gastrointestinal disorders | — | — | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — | — | — |
| Platelet count decreased | Investigations | — | — | — | — | — |
| White blood cell decreased | Investigations | — | — | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — | — | — |
| Fatigue | General disorders | — | — | — | — | — |
| Hypoalbuminemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — | — | — |
| Alopecia | Skin and subcutaneous tissue disorders | — | — | — | — | — |
| Anorexia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hyperglycemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypocalcemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hyponatremia | Metabolism and nutrition disorders | — | — | — | — | — |
| Lymphocyte count decreased | Investigations | — | — | — | — | — |
| Neutrophil count decreased | Investigations | — | — | — | — | — |
| Sinus tachycardia | Cardiac disorders | — | — | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — | — | — |
| Alkaline phosphatase increased | Investigations | — | — | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — | — | — |
| Constipation | Gastrointestinal disorders | — | — | — | — | — |
| Fever | General disorders | — | — | — | — | — |
| Headache | Nervous system disorders | — | — | — | — | — |
| Hypermagnesemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypoglycemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypokalemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypomagnesemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypophosphatemia | Metabolism and nutrition disorders | — | — | — | — | — |
| Hypotension | Vascular disorders | — | — | — | — | — |
| Pain | General disorders | — | — | — | — | — |
| Allergic rhinitis | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — |
| Blood bilirubin increased | Investigations | — | — | — | — | — |
| Cough | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — |
| Creatinine increased | Investigations | — | — | — | — | — |
| Depression | Psychiatric disorders | — | — | — | — | — |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — |
| Edema limbs | General disorders | — | — | — | — | — |
| Gait disturbance | General disorders | — | — | — | — | — |
| Hypercalcemia | Metabolism and nutrition disorders | — | — | — | — | — |
Most-reported serious reactions: Lymphocyte count decreased, White blood cell decreased, Neutrophil count decreased, Alanine aminotransferase increased, Hyperglycemia, Hypokalemia, Abdominal pain, Anemia.
Data from ClinicalTrials.gov NCT03323034 adverse events section.
This phase I trial studies the side effects and best dose of pevonedistat when given together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma that have come back after a period of improvement (recurrent) or that do not respond to treatment (refractory). Pevonedistat and irinotecan may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, 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. Giving pevonedistat, irinotecan hydrochloride, and temozolomide may work better in treating patients with solid tumors, central nervous system (CNS) tumors, or lymphoma compared to irinotecan and temozolomide alone.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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