Recurrent Neuroendocrine Tumor, Metastatic Neuroendocrine Tumor
Conditions
Keywords
Pheochromocytoma-paraganglioma, ONC201
Brief summary
The purpose of this study is to learn if a new drug, ONC201 can make tumors become smaller or go away completely. Investigators also want to learn if ONC201 can prevent new deposits of cancer from appearing in new places in participants (metastases). A phase 2 study of ONC201 in PC-PG (pheochromocytoma-paraganglioma) and other neuroendocrine tumors will determine whether inhibition of DRD2 (a member of the dopamine receptor family) is safe in unresectable, recurrent, locally advanced, refractory, or metastatic neuroendocrine cancers including PC-PG, desmoplastic small round cell tumor (DSRCT), Ewing sarcoma (PNET) or any other neuroendicrine tumor with a catecholamine or dopamine biomarker or autocrine or paracrine dependence on dopamine including cholangiocarcinoma and adrenal cortical carcinoma. ONC201 is an investigational (experimental) agent and has a favorable safety profile in phase 1 and early phase 2 clinical trials in advanced cancers. This study design has been chosen to see whether ONC201 is associated with reduction of anti-hypertension medications, safety and significant efficacy against neuroendocrine tumors, especially PC-PG.
Detailed description
Primary Objective To demonstrate objective responses using MRI or CT, and/or PET-CT imaging. The same CT or MRI imaging to assess disease burden at study entry will be compared at week 6 and 3 months. Patients without progression at 3 months will continue treatment and have imaging at 6, 9 and 12 months after study entry. Metabolic response and/or biomarkers will be compared with study entry PET-CT and scans at 6 weeks, 3 months and 12 months. Secondary Objectives Progression - free Survival: This will be calculated according to Response Evaluation Criteria In Solid Tumors (RECIST) or development of new disease Overall survival: Overall survival will be determined by email or telephone contact. Study Design: Phase 2 open-label fixed dose study Metastatic neuroendocrine tumors including PC-PG are rare diseases. The current recommended phase II dose of 625 mg orally on 2 consecutive days every week will be used. The same imaging at study entry will be used at subsequent time points (CT or MRI for week 6 and 3, 6, 9, and 12 months) Imaging modality choice will be influenced by the quality of prior scans of the subject and will be ordered so clinical comparison is possible. Because of travel and lodging considerations associated with the COVID-19 pandemic, some information by the study team/PI may be obtained using virtual visits and 2nd read of scans sent to Cleveland Clinic
Interventions
DRUGONC201
625mg ONC201 will be given on two consecutive days each week
Sponsors
Peter Anderson
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects must have a unresectable, recurrent, locally advanced, refractory, or metastatic neuroendocrine tumor including pheochromocytoma-paraganglioma (PC-PG), DSRCT, Ewing Sarcoma or PNET, or any neuroendocrine tumor with a catecholamine or dopamine biomarker or autocrine or paracrine dependence on dopamine including cholangiocarcinoma and adrenal cortical carcinoma (ACC). 2. There is no limit on number of prior therapies. 3. Age ≥14 years. 4. Subjects must have normal organ and marrow function as defined below. Studies should be done within 3 weeks prior to enrollment * Hemoglobin ≥ 10.0 g/dl * Leukocytes ≥ 1500/mcL * Absolute neutrophil count ≥ 1,000/mcL * Platelet count ≥ 75000/mcL * Total bilirubin within 1.5 x normal institutional limits * AST (SGOT) ≤ 5 X institutional upper limit of normal * ALT (SGPT) ≤ 5 X institutional upper limit of normal * Serum Creatinine \<3.0mg/dL * 5 1 lesion detectable on CT, MRI, 18FDG PET-CT 6 Subjects must have the ability to understand and the willingness to sign a written informed consent document. 7: Karnofsky or if \<16 years old Lansky Play Performance status ≥ 60%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response According to RECIST Criteria | Up to 1 Year | Complete Response (CR) Disappearance or fibrosis of all target lesions. Any pathologic lymph nodes must have reduction in short axis to \<10mm and standardized uptake value (SUV) is \<4. Partial Response (PR) At least 30% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) and any decrease in SUV in Fludeoxyglucose 18F (18FDG) imaging Stable disease (SD) 0-29% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) or 0-19% increase in sum of longest diameters of target lesions (compared to initial on study baseline). SUV may increase or decrease Progressive disease 20% or more increase of sum of longest diameters of target lesions (compared to initial on study baseline). The sum must also be at an increase of at least 5mm or one or more new lesions that are considered metastatic disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Duration of Therapy | Up to 5 years | The median Duration of therapy was measured. Participants with stable disease + PR allowed to continue; participants with progression were taken off therapy. |
| Overall Survival | Up to 1 Year | Time from beginning of treatment until death, or one year, whichever comes first. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Metastatic PC-PG 625mg ONC201 will be given once weekly
ONC201: 625mg ONC201 will be given on two consecutive days each week | 10 |
| Arm B: Other NETs 625mg ONC201 will be given once weekly
ONC201: 625mg ONC201 will be given on two consecutive days each week | 12 |
| Arm C: PC-PG + Other NETs 625mg ONC201 will be given on day 1 and day 2 of each week
ONC201: 625mg ONC201 will be given on two consecutive days each week | 8 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adjuvant Therapy | 0 | 0 | 1 |
| Overall Study | Disease progression | 8 | 10 | 4 |
| Overall Study | Patient off treatment for other complicating disease | 0 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 3 |
Baseline characteristics
| Characteristic | Arm B: Other NETs | Arm C: PC-PG + Other NETs | Arm A: Metastatic PC-PG | Total |
|---|---|---|---|---|
| Age, Customized 0-9 years of age | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 10-19 years of age | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Customized 20-29 years of age | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Age, Customized 30-39 years of age | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Age, Customized 40-49 years of age | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Age, Customized 50-59 years of age | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized 60-69 years of age | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Age, Customized 70-79 years of age | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 8 Participants | 9 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 8 Participants | 8 Participants | 27 Participants |
| Region of Enrollment United States | 12 participants | 8 participants | 10 participants | 30 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 10 | 8 / 12 | 2 / 8 |
| other Total, other adverse events | 4 / 10 | 1 / 12 | 8 / 8 |
| serious Total, serious adverse events | 3 / 10 | 1 / 12 | 4 / 8 |
Outcome results
Primary
Tumor Response According to RECIST Criteria
Complete Response (CR) Disappearance or fibrosis of all target lesions. Any pathologic lymph nodes must have reduction in short axis to \<10mm and standardized uptake value (SUV) is \<4. Partial Response (PR) At least 30% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) and any decrease in SUV in Fludeoxyglucose 18F (18FDG) imaging Stable disease (SD) 0-29% decrease in sum of longest diameters of target lesions (compared to initial on study baseline) or 0-19% increase in sum of longest diameters of target lesions (compared to initial on study baseline). SUV may increase or decrease Progressive disease 20% or more increase of sum of longest diameters of target lesions (compared to initial on study baseline). The sum must also be at an increase of at least 5mm or one or more new lesions that are considered metastatic disease
Time frame: Up to 1 Year
Population: All participants were analyzed.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Metastatic PC-PG | Tumor Response According to RECIST Criteria | Complete Response (CR) | 0 Participants |
| Arm A: Metastatic PC-PG | Tumor Response According to RECIST Criteria | Partial Response (PR) | 5 Participants |
| Arm A: Metastatic PC-PG | Tumor Response According to RECIST Criteria | Stable Disease (SD) | 2 Participants |
| Arm A: Metastatic PC-PG | Tumor Response According to RECIST Criteria | Progressive disease | 3 Participants |
| Arm B: Other NETs | Tumor Response According to RECIST Criteria | Progressive disease | 9 Participants |
| Arm B: Other NETs | Tumor Response According to RECIST Criteria | Complete Response (CR) | 0 Participants |
| Arm B: Other NETs | Tumor Response According to RECIST Criteria | Stable Disease (SD) | 2 Participants |
| Arm B: Other NETs | Tumor Response According to RECIST Criteria | Partial Response (PR) | 1 Participants |
| Arm C: PC-PG + Other NETs | Tumor Response According to RECIST Criteria | Progressive disease | 0 Participants |
| Arm C: PC-PG + Other NETs | Tumor Response According to RECIST Criteria | Partial Response (PR) | 1 Participants |
| Arm C: PC-PG + Other NETs | Tumor Response According to RECIST Criteria | Stable Disease (SD) | 7 Participants |
| Arm C: PC-PG + Other NETs | Tumor Response According to RECIST Criteria | Complete Response (CR) | 0 Participants |
Secondary
Median Duration of Therapy
The median Duration of therapy was measured. Participants with stable disease + PR allowed to continue; participants with progression were taken off therapy.
Time frame: Up to 5 years
Population: All participants were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Metastatic PC-PG | Median Duration of Therapy | 9 months |
| Arm B: Other NETs | Median Duration of Therapy | 3 months |
| Arm C: PC-PG + Other NETs | Median Duration of Therapy | 10 months |
Secondary
Overall Survival
Time from beginning of treatment until death, or one year, whichever comes first.
Time frame: Up to 1 Year
Population: All participants were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Metastatic PC-PG | Overall Survival | 4 Participants |
| Arm B: Other NETs | Overall Survival | 4 Participants |
| Arm C: PC-PG + Other NETs | Overall Survival | 7 Participants |
Post Hoc
Number of Participants With Decline in Karnofsky Performance Status
Participant performance status was measured using Karnofsky Performance Status Scale with the goal of determining the number of participants with a decline in score at 12 weeks. Karnofsky Performance Scale Index is an assessment tool for functional impairment. Scores can range from 0 to 100, with 100 indicating normal performance with no complaints or evidence of disease, while 0 indicates death.
Time frame: 3 months
Population: All participants were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Metastatic PC-PG | Number of Participants With Decline in Karnofsky Performance Status | 1 Participants |
| Arm B: Other NETs | Number of Participants With Decline in Karnofsky Performance Status | 1 Participants |
| Arm C: PC-PG + Other NETs | Number of Participants With Decline in Karnofsky Performance Status | 0 Participants |