Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors
Conditions
Keywords
Dose Escalation, Dose Expansion, Prostate-specific antigen, Maximum tolerated dose, Recommended Phase 2 dose
Brief summary
This is a Phase 1b/Phase 2a, open-label, multicenter study to determine the safety, tolerability, recommended Phase 2 dose (RP2D), efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) properties of idronoxil when rectally administered as a suppository (NOX66) to patients with any solid tumor (Part 1) and patients with metastatic castration-resistant prostate cancer (mCRPC), breast cancer (BC) and non-small-cell lung cancer (NSCLC) (Part 2) who are eligible for low-dose external beam radiotherapy (EBRT) for at least one symptomatic or minimally symptomatic lesion (for the prevention of symptoms).
Detailed description
The study is divided into 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The study design allows an exploration of different doses of NOX66 (800 mg, 1200 mg, 1600 mg and 2400 mg) with safety monitoring to ensure the safety of the patients. In Cycle 1, NOX66 will be administered for 14 days followed by a 7-day rest period on a 21-day cycle. From Cycle 2 onwards, NOX66 will be administered for 7 days followed by a 7-day rest period on a 14-day cycle. Patients will continue to receive NOX66 on a cyclical basis until disease progression, unacceptable toxicity, withdrawal of consent, start of a new anticancer therapy, withdrawal of the patient by the Investigator or the end of study is reached.
Interventions
Sponsors
Noxopharm Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has a minimum life expectancy of 6 months * Histological or cytological confirmation of prostate cancer, BC, NSCLC and any other solid tumors * Confirmed metastatic disease by imaging * Documented disease progression following first or later lines of anticancer systemic treatment * Patient is eligible for low-dose EBRT for at least one lesion * Patients with prior RT are eligible, only if there is no potential for field overlap between the prior RT and the planned RT * For patients with BC or NSCLC: Patient must have at least one measurable lesion as per RECIST v1.1 (in Part 2 only) * Patient has ECOG performance status of 0 to 2 * Adequate bone marrow, renal, and liver function * Metastatic Castration-resistant Prostate Cancer: Baseline testosterone levels ≤ 14.4 ng/dL and ongoing medical castration must be maintained throughout the duration of the study; patient has evidence of symptomatic and/or progressive disease * Breast Cancer Patients: Known hormone receptor status (estrogen receptors/progesterone receptors or estrogen receptors alone). Breast cancer patients are allowed to be on background hormonal treatment.
Exclusion criteria
* Patient has tumor involvement of the central nervous system * Impaired cardiac functioning or clinically significant cardiac disease * Uncontrolled hypertension despite two concomitant antihypertensive therapies * Patients who have had a colectomy (total or left hemicolectomy) with re-anastomosis * Patients for whom administration of the suppositories are likely to cause pain or difficulties in absorption * Patients with fecal impaction or uncontrolled irritable bowel disease * Patients with inflammatory bowel disease * Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that, in the Investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent * Patients with oligometastatic disease (fewer than 5 metastatic lesions) amenable to standard therapy will be excluded * Patients who have had RT to the region of the rectum or will require RT to the region of the rectum during the trial * Uncontrolled active infection requiring intravenous antibiotic, antiviral or anti-fungal medications within 14 days before the first dose administration * Receiving or having received anticancer treatment * Patient has received corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for any reason within 4 weeks prior to receiving the first dose administration * Patient is not willing to use suppositories * Patient has a positive reverse transcription polymerase chain reaction (RT-PCR) test for severe acute respiratory coronavirus 2 (SARS-CoV-2) prior to Screening or enrollment, or has clinical signs and symptoms consistent with SARS-CoV-2 infection; e.g., fever, dry cough, dyspnea, sore throat, fatigue or positive SARS-CoV-2 test result within 2 weeks prior to Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs) | Cycle 1 (Day 1 to Day 21) | Maximum tolerated dose (MTD) and RP2D of NOX66 in combination with low-dose EBRT in patients with any solid tumor. MTD is defined as the dose level at which no more than 1 patient out of 6 has a DLT at the end of Cycle 1. RP2D is the highest dose at which no more than 1 patient out of 6 has a DLT at the end of Cycle 1 and the dosage form, is acceptable to patients. A DLT is defined as an AE that occurs during Cycle 1 (Day 1 to Day 21) that is unrelated to the disease, intercurrent illness or concomitant medications and that, possibly- definitely related to NOX66 alone or in combination with EBRT: Grade (G) ≥3 non-hematological toxicity; G≥3 febrile neutropenia; G4 thrombocytopenia \> 5 days; G3 thrombocytopenia with bleeding or in combination with a G ≥3 blood and lymphatic system disorder.; G3 AST or ALT that is + a ≥G2 rise in bilirubin \>7 days; AST or ALT \> 8 × ULN; AE causing treatment delay \> 14 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Incidence of Adverse Events (AEs) for NOX66 | From Screening (Days -28 to -2) until the Follow-up visit/End of Study (EOS) (through study completion, an average of 19 month) | Characterization of the safety and tolerability of NOX66. |
| Part 1: TEAEs by Relationship to EBRT Administration | From Screening (Days -28 to -2) until the Follow-up visit/EOS (through study completion, an average of 19 month) | Evaluation of the safety and tolerability of both doses of EBRT (8 Gy or 20/25 Gy). |
Countries
United States
Participant flow
Recruitment details
21 patients
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dose Cohort 1: NOX66 800 mg NOX66: NOX66 800 mg daily (400 mg suppository twice daily \[BID\]).
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 4 |
| Part 1: Dose Cohort 2: NOX66 1200 mg NOX66: NOX66 1200 mg daily (600 mg suppository BID).
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 7 |
| Part 1: Dose Cohort 3: NOX66 1600 mg NOX66: NOX66 1600 mg daily (800 mg suppository BID).
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 10 |
| Part 1: Dose Cohort 4: NOX66 2400 mg NOX66: NOX66 2400 mg daily (1200 mg suppository BID).
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 0 |
| Part 2: Arm 1: Patients With mCRPC (RP2D NOX66) NOX66: NOX66 RP2D
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 0 |
| Part 2: Arm 2: Patients With BC or NSCLC (RP2D NOX66) NOX66: NOX66 RP2D
EBRT: The dose levels of EBRT will be either 8 Gy as a single fraction, or 20/25 Gy as 5 fractions given over 5 to 10 days. | 0 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 2 | 1 | 0 | 0 | 0 |
| Overall Study | non compliance with study drug | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | none specified. | 0 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 3 | 2 | 0 | 0 | 0 |
| Overall Study | study terminated by sponsor | 0 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | unacceptable toxicity | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Dose Cohort 3: NOX66 1600 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 69 years | 73 years | 67.5 years | 68 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 5 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 0 Participants | 3 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 9 Participants | 17 Participants |
| Region of Enrollment Australia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Hungary | 0 participants | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 4 participants | 6 participants | 8 participants | 18 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 2 / 7 | 1 / 10 |
| other Total, other adverse events | 4 / 4 | 6 / 7 | 9 / 10 |
| serious Total, serious adverse events | 1 / 4 | 3 / 7 | 5 / 10 |
Outcome results
Primary
Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs)
Maximum tolerated dose (MTD) and RP2D of NOX66 in combination with low-dose EBRT in patients with any solid tumor. MTD is defined as the dose level at which no more than 1 patient out of 6 has a DLT at the end of Cycle 1. RP2D is the highest dose at which no more than 1 patient out of 6 has a DLT at the end of Cycle 1 and the dosage form, is acceptable to patients. A DLT is defined as an AE that occurs during Cycle 1 (Day 1 to Day 21) that is unrelated to the disease, intercurrent illness or concomitant medications and that, possibly- definitely related to NOX66 alone or in combination with EBRT: Grade (G) ≥3 non-hematological toxicity; G≥3 febrile neutropenia; G4 thrombocytopenia \> 5 days; G3 thrombocytopenia with bleeding or in combination with a G ≥3 blood and lymphatic system disorder.; G3 AST or ALT that is + a ≥G2 rise in bilirubin \>7 days; AST or ALT \> 8 × ULN; AE causing treatment delay \> 14 days.
Time frame: Cycle 1 (Day 1 to Day 21)
Population: All patients that completed cycle 1.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs) | 0 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs) | 0 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1 (Dose Escalation): Number of Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
Part 1: Incidence of Adverse Events (AEs) for NOX66
Characterization of the safety and tolerability of NOX66.
Time frame: From Screening (Days -28 to -2) until the Follow-up visit/End of Study (EOS) (through study completion, an average of 19 month)
Population: Safety population = all participants who received at least one dose of NOX66
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 4 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 4 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Dose Limiting Toxicity | 0 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Fatal TEAE | 0 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | AEs that were greater than Grade 2 severity | 1 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | TEAE related to Study Treatment (NOX66) | 4 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | TEAE related to Study Treatment (NOX66) | 4 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 7 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Fatal TEAE | 1 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | AEs that were greater than Grade 2 severity | 5 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 7 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Dose Limiting Toxicity | 0 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one TEAE (Treatment Emergent Adverse Event) | 9 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Dose Limiting Toxicity | 0 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | TEAE related to Study Treatment (NOX66) | 6 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | Fatal TEAE | 0 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | With at least one Adverse Event | 9 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: Incidence of Adverse Events (AEs) for NOX66 | AEs that were greater than Grade 2 severity | 5 Participants |
Secondary
Part 1: TEAEs by Relationship to EBRT Administration
Evaluation of the safety and tolerability of both doses of EBRT (8 Gy or 20/25 Gy).
Time frame: From Screening (Days -28 to -2) until the Follow-up visit/EOS (through study completion, an average of 19 month)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: TEAEs by Relationship to EBRT Administration | Related | 0 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: TEAEs by Relationship to EBRT Administration | No AEs related to EBRT | 3 Participants |
| Part 1: Dose Cohort 1: NOX66 800 mg | Part 1: TEAEs by Relationship to EBRT Administration | Possibly Related | 1 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: TEAEs by Relationship to EBRT Administration | No AEs related to EBRT | 3 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: TEAEs by Relationship to EBRT Administration | Possibly Related | 2 Participants |
| Part 1: Dose Cohort 2: NOX66 1200 mg | Part 1: TEAEs by Relationship to EBRT Administration | Related | 2 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: TEAEs by Relationship to EBRT Administration | Related | 2 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: TEAEs by Relationship to EBRT Administration | Possibly Related | 3 Participants |
| Part 1: Dose Cohort 3: NOX66 1600 mg | Part 1: TEAEs by Relationship to EBRT Administration | No AEs related to EBRT | 5 Participants |