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This is a Phase Ib/II study assessing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended Phase 2 dose (RP2D), and efficacy of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose of L-NMMA will be 7.5 mg/kg. In the Phase II portion of the study, the starting dose will be the RP2D determined in the Phase Ib portion of the study.
This is a Phase Ib/II study assessing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended Phase 2 dose (RP2D), and efficacy of L-NMMA when combined with docetaxel in refractory locally advanced or metastatic triple negative breast cancer patients. The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose of L-NMMA will be 7.5 mg/kg. L-NMMA dose will escalate/de-escalate based on DLT occurrence. For the 5, 7.5, 10, 12.5, and 15 mg/kg L-NMMA doses, docetaxel will be administered at 75 mg/m2. For the 17.5 and 20 mg/kg L-NMMA doses, docetaxel will be administered at 100 mg/m2. In the Phase II portion of the study, the starting dose will be the RP2D determined in the Phase Ib portion of the study. In the phase II portion of the study, patients will be treated with L-NMMA and taxane (docetaxel, paclitaxel, or nab-paclitaxel) per physician's choice. Patients will be treated with L-NMMA and taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel) per physician's choice. L-NMMA will be administered on Days 1-5 and taxane chemotherapy on Day 1 Q3W or Day 1 Q1W. L-NMMA and docetaxel will be administered at the RP2D determined in the phase Ib portion of the study. Paclitaxel at 175 mg/m2 will be IV infused over 3 hours or 80 mg/m2 will be IV infused over 1 hour, and nab-paclitaxel at 260 mg/m2 will be IV infused over 30 minutes. For L-NMMA-induced hypertension, amlodipine (10 mg) and enteric-coated low-dose aspirin (81 mg) will be orally administered. Amlodipine will be administered for 6 days at each cycle, starting 24 hours before the first dose of L-NMMA. Enteric-coated low-dose aspirin will be administered once daily during the 6 21-day cycles. For docetaxel-induced leukopenia, pegfilgrastim (6 mg) will be administered via subcutaneous injection approximately 24 hours after every dose of docetaxel.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
| L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
| L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
| L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| L-NMMA | Drug | Nitric oxide synthase inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| Asses the Maximum Tolerated Dose (MTD) of L-NMMA When Combined With Docetaxel/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level. | The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method. | DLTs assessment window is the duration required for completing one full cycle (through Day 21). |
| Clinical Benefit Rate | Primary Outcome Measure for Phase II: Determine the number of participants with complete response, partial response, or stable disease after 6 cycles of L-NMMA combined with taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel)/amlodipine, as assessed by the RECIST 1.1.
| The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). |
| Asses the Maximum Tolerated Dose (MTD) of Docetaxel When Combined With L-NMMA/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level. | The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method. |
| Measure | Description | Time Frame |
|---|---|---|
| Dose Limiting Toxicities (DLTs) and Other Adverse Events | Describe the DLTs and other adverse events associated with L-NMMA when combined with docetaxel/amlodipine, as assessed by the CTCAE v4.03 Any Grade ≥ 3 Adverse Events (AE) unless there is clear alternative evidence that the AE was not caused by the study treatment. | The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). |
| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Plasma Concentration Curve of the L-NMMA and Docetaxel Combination | Determine the area under the plasma concentration curve of the L-NMMA and docetaxel combination | 18 weeks |
| Predictive Biomarkers |
Inclusion Criteria:
Patient must meet all of the following criteria:
• Female patients with pathologically determined advanced (progressive disease or refractory to 3 cycles of standard chemotherapy) or metastatic (any line) triple negative breast cancer (TNBC). TNBC is defined as: Estrogen receptor negative and progesterone receptor negative (<10% staining by immunohistochemistry [IHC]).
Human epidermal growth factor receptor 2 (HER2) negative. HER2 negativity must be confirmed by one of the following:
Fluorescence in situ hybridization (FISH)-negative (FISH ratio <2), or
IHC 0-1+, or
IHC 2+ AND FISH-negative (FISH ratio <2). Eastern Cooperative Oncology Group performance status of ≤ 2
Hemoglobin ≥9.0 g/dL (transfusions permitted)
Absolute neutrophil count ≥1500/mm3 (1.5 x 109/L)
Platelet count ≥100,000/mm3 (100 x 109/L)
Total bilirubin <2 X upper limit of normal (ULN)
Creatinine (Cr) <2 X ULN and Cr clearance (CrCl) ≥30 by Cockcroft and Gault
Alanine transaminase (ALT) and aspartate transaminase (AST) <2 X ULN (if liver metastases are present then ALT and AST must be <5 X ULN)
Exclusion Criteria:
History of poorly controlled hypertension (defined as systolic blood pressure >150 mmHg at baseline)
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| Name | Affiliation | Role |
|---|---|---|
| Polly Niravath, M.D. | Houston Methodist Cancer Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Houston Methodist Hospital | Houston | Texas | 77030 | United States |
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2 subjects withdrew in phase 2 and were in-evaluable.
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental: L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 19, 2019 |
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| L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
| L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Experimental | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
| Phase II: RP2D determined in the Phase Ib | Experimental | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
|
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| Docetaxel | Drug | Mitotic inhibitor, cytotoxic |
|
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| Amlodipine | Drug | Long-acting calcium channel blocker |
|
|
| Pegfilgrastim | Drug | Colony-stimulating factor |
|
|
| Enteric-coated aspirin | Drug | non-steroidal anti-inflammatory drug |
|
|
| DLTs assessment window is the duration required for completing one full cycle (through Day 21). |
| Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | Determine the RP2D of the L-NMMA and docetaxel combination based on the occurrence of DLTs during Phase Ib portion of the study. As patients are accrued, they will start with 7.5 mg/kg of L-NMMA and 75 mg/m2 of docetaxel and their DLTs will be assessed after completion of the first cycle. This will determine the next cohort dose, until at least 4 patients receive the dose with minimal DLTs that won't require dose reduction. | The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21). |
| Antitumor Activity | Assess the antitumor activity of L-NMMA when combined with taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel)/amlodipine, as assessed by the RECIST 1.1.
| The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). |
| Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Determine the time to maximum plasma concentration of the L-NMMA and docetaxel combination. | Blood samples will be collected predose (10-30 minutes before L-NMMA infusion) on Days 1, 2, and 5 of Cycle 1 and Days 1 and 5 of Cycle 2 for determination of L-NMMA plus docetaxel plasma PK. |
Determine potential predictive biomarkers including serum levels of nitrate/nitrite; serum levels of inflammatory biomarkers; angiogenesis-related biomarkers; and RPL39, MLF2, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations in cell-free DNA
| 18 weeks |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 |
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG002 | Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG003 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG004 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG005 | Experimental: L-NMMA 20 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| FG006 | Experimental: Phase II: RP2D Determined in the Phase Ib | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
| Evaluable Patients |
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| COMPLETED |
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| NOT COMPLETED |
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|
37 patients started the trial, 2 were in-evaluable from phase 2. The results are based on the 35 evaluable patients.
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental: L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| BG001 | Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| BG002 | Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| BG003 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1 |
| BG004 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| BG005 | Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| BG006 | Experimental: Phase II: RP2D Determined in the Phase Ib | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
| BG007 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | Years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
| ||||||||||||||||
| Stage of Breast Cancer Diagnosis | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Asses the Maximum Tolerated Dose (MTD) of L-NMMA When Combined With Docetaxel/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level. | The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method. | 15 participants participated in Phase Ib portion of the trial until the MTD was determined after 4 patient completed at least one cycle of treatment at the same dose without DLTs. | Posted | Number | mg/kg | DLTs assessment window is the duration required for completing one full cycle (through Day 21). |
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| Primary | Clinical Benefit Rate | Primary Outcome Measure for Phase II: Determine the number of participants with complete response, partial response, or stable disease after 6 cycles of L-NMMA combined with taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel)/amlodipine, as assessed by the RECIST 1.1.
| 24 subjects participated in the Phase II portion of the trial | Posted | Count of Participants | Participants | The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). |
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| Secondary | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Describe the DLTs and other adverse events associated with L-NMMA when combined with docetaxel/amlodipine, as assessed by the CTCAE v4.03 Any Grade ≥ 3 Adverse Events (AE) unless there is clear alternative evidence that the AE was not caused by the study treatment. | Patients who experienced adverse events Grade ≥ 3 | Posted | Count of Units | Grade ≥ 3 AE | The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). | Grade ≥ 3 AE | Grade ≥ 3 AE |
| ||||||||||||||||||||||||||
| Secondary | Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | Determine the RP2D of the L-NMMA and docetaxel combination based on the occurrence of DLTs during Phase Ib portion of the study. As patients are accrued, they will start with 7.5 mg/kg of L-NMMA and 75 mg/m2 of docetaxel and their DLTs will be assessed after completion of the first cycle. This will determine the next cohort dose, until at least 4 patients receive the dose with minimal DLTs that won't require dose reduction. | 15 participants participated in Phase Ib portion of the trial until the MTD was determined after 4 patient completed at least one cycle of treatment at the same dose without DLTs. | Posted | Number | mg/kg | The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21). |
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| Secondary | Antitumor Activity | Assess the antitumor activity of L-NMMA when combined with taxane chemotherapy (docetaxel, paclitaxel, or nab-paclitaxel)/amlodipine, as assessed by the RECIST 1.1.
| 22 subjects participated in the Phase II portion of the trial (2 patients were in-evaluable) 4 subjects were included from Phase Ib portion who received the same dose. | Posted | Count of Participants | Participants | The approximate length of the study from Cycle 1, Day 1 will be approximately seven months (approximately four months of treatment plus three months of follow-up). |
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| Secondary | Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Determine the time to maximum plasma concentration of the L-NMMA and docetaxel combination. | To determine the PK of L-NMMA, we assayed serum samples from two patients receiving L-NMMA at 15 mg/kg and docetaxel at 75 mg/m2 and two patients receiving L-NMMA at 17.5 mg/kg and docetaxel at 100 mg/m2. | Posted | Mean | Full Range | Hours | Blood samples will be collected predose (10-30 minutes before L-NMMA infusion) on Days 1, 2, and 5 of Cycle 1 and Days 1 and 5 of Cycle 2 for determination of L-NMMA plus docetaxel plasma PK. |
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| Other Pre-specified | Area Under the Plasma Concentration Curve of the L-NMMA and Docetaxel Combination | Determine the area under the plasma concentration curve of the L-NMMA and docetaxel combination | Not Posted | 18 weeks | Participants | |||||||||||||||||||||||||||||||
| Other Pre-specified | Predictive Biomarkers | Determine potential predictive biomarkers including serum levels of nitrate/nitrite; serum levels of inflammatory biomarkers; angiogenesis-related biomarkers; and RPL39, MLF2, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations in cell-free DNA | Not Posted | 18 weeks | Participants | |||||||||||||||||||||||||||||||
| Primary | Asses the Maximum Tolerated Dose (MTD) of Docetaxel When Combined With L-NMMA/Amlodipine in the Treatment of Refractory Locally Advanced or Metastatic TNBC Patients, Based on the Number of Dose Limiting Toxicities (DLTs) Per Dose Level. | The Phase Ib portion of the study is designed to investigate the combination at two dose levels of docetaxel (75 and 100 mg/m2) and 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg). The starting dose will be L-NMMA at 7.5 mg/kg and docetaxel at 75 mg/m2. As patients are accrued, a standard Bayesian model averaging continual reassessment method (CRM) approach will be used to determine the appropriate dosage. For a dose level to be chosen as the MTD, at least 4 patients must have received said dose without experiencing a significant number of DLTs based on the Bayesian Model Averaging Continual Reassessment Method. | 15 participants participated in Phase Ib portion of the trial until the MTD was determined after 4 patient completed at least one cycle of treatment at the same dose without DLTs. | Posted | Number | mg/m^2 | DLTs assessment window is the duration required for completing one full cycle (through Day 21). |
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| Secondary | Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | Determine the RP2D of the L-NMMA and docetaxel combination based on the occurrence of DLTs during Phase Ib portion of the study. As patients are accrued, they will start with 7.5 mg/kg of L-NMMA and 75 mg/m2 of docetaxel and their DLTs will be assessed after completion of the first cycle. This will determine the next cohort dose, until at least 4 patients receive the dose with minimal DLTs that won't require dose reduction. | 15 participants participated in Phase Ib portion of the trial until the MTD was determined after 4 patient completed at least one cycle of treatment at the same dose without DLTs. | Posted | Number | mg/m^2 | The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21). |
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From informed consent signing up to and including 30 days after the last treatment dose. All patients will be followed for 3 months after the final dose of treatment and will be evaluated accordingly with the required standard of care labs and tests. All reported events are included when the subjects was on study, or within the follow up period, up to 3 months after the final dose. A maximum duration of 8 months.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Experimental: L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 7.5 mg/kg (starting dose) will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. Amlodipine: Long-acting calcium channel blocker Pegfilgrastim: Colony-stimulating factor Enteric-coated aspirin: non-steroidal anti-inflammatory drug | 0 | 2 | 1 | 2 | 2 | 2 |
| EG001 | Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 10 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. | 0 | 2 | 2 | 2 | 2 | 2 |
| EG002 | Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. | 0 | 2 | 0 | 2 | 2 | 2 |
| EG003 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. | 0 | 2 | 0 | 2 | 1 | 2 |
| EG004 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. | 0 | 3 | 1 | 3 | 3 | 3 |
| EG005 | Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. | 0 | 4 | 1 | 4 | 4 | 4 |
| EG006 | Experimental: Phase II: RP2D Determined in the Phase Ib | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study | 0 | 20 | 3 | 20 | 17 | 20 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Change in mental status | Psychiatric disorders | Systematic Assessment | Change in mental status (due to multiple brain mets & possible leptomeningeal disease) |
| |
| Pleural Effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Right upper extremity Cellulitis | Infections and infestations | Systematic Assessment | A disorder characterized by an infectious process involving the skin such as cellulitis. |
| |
| Tumor pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
| ||
| Acute renal insufficiency | Renal and urinary disorders | Systematic Assessment |
| ||
| Chest wall significant Erythema on front and back | Cardiac disorders | Systematic Assessment | L. Chest wall-Significant Erythema on front and back, Skin peeling and hardness of chest wall |
| |
| Clinical sepsis | Infections and infestations | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
| ||
| Acute allergic reaction | Immune system disorders | Systematic Assessment |
| ||
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Bicytopenia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Bilateral Leg Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Bloating | Gastrointestinal disorders | Systematic Assessment |
| ||
| Body Aches | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Cellulitis | Infections and infestations | Systematic Assessment |
| ||
| Chest pain | Cardiac disorders | Systematic Assessment |
| ||
| Constipation | Gastrointestinal disorders | Systematic Assessment |
| ||
| Contusion | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Decreased appetite | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Decreased Hemoglobin | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Dehydration | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Dizziness | Nervous system disorders | Systematic Assessment |
| ||
| Dyspepsia | Gastrointestinal disorders | Systematic Assessment |
| ||
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Edema | General disorders | Systematic Assessment |
| ||
| Elevated AST and ALT | Hepatobiliary disorders | Systematic Assessment |
| ||
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Erythema | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Fatigue and weakness | General disorders | Systematic Assessment |
| ||
| Gum bleeding | Infections and infestations | Systematic Assessment |
| ||
| Hand-foot Syndrome | Infections and infestations | Systematic Assessment |
| ||
| Headache | Nervous system disorders | Systematic Assessment |
| ||
| Heartburn | Gastrointestinal disorders | Systematic Assessment |
| ||
| Hypokalemia | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Hypotension | Vascular disorders | Systematic Assessment |
| ||
| Blepharitis | Eye disorders | Systematic Assessment |
| ||
| Insomnia | Psychiatric disorders | Systematic Assessment |
| ||
| Neuropathy | Nervous system disorders | Systematic Assessment |
| ||
| Arm and shoulder swelling | General disorders | Systematic Assessment |
| ||
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Lower abdomen incision packing | General disorders | Systematic Assessment |
| ||
| Narrowing of brachiocephalic vein stenosis | Renal and urinary disorders | Systematic Assessment |
| ||
| Nausea | Gastrointestinal disorders | Systematic Assessment |
| ||
| Oral mucositis | Infections and infestations | Systematic Assessment |
| ||
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Palpitations | Cardiac disorders | Systematic Assessment |
| ||
| Rosacea | Skin and subcutaneous tissue disorders | Systematic Assessment |
| ||
| Sensitivity to light | Nervous system disorders | Systematic Assessment |
| ||
| Syncope | Nervous system disorders | Systematic Assessment |
| ||
| Tachycardia | Cardiac disorders | Systematic Assessment |
| ||
| Transaminitis | Hepatobiliary disorders | Systematic Assessment |
| ||
| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
| ||
| Vaginal candidiasis | Infections and infestations | Systematic Assessment |
| ||
| Vomitting | Gastrointestinal disorders | Systematic Assessment |
| ||
| Weight loss | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Fever | General disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Polly Niravath, MD | Houston Methodist Cancer Center | 713-441-0629 | ccresearch@houstonmethodist.org |
| Oct 25, 2022 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D064726 | Triple Negative Breast Neoplasms |
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D019323 | omega-N-Methylarginine |
| D000077143 | Docetaxel |
| D017311 | Amlodipine |
| C455861 | pegfilgrastim |
| D001241 | Aspirin |
| ID | Term |
|---|---|
| D001120 | Arginine |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |
| D043823 | Taxoids |
| D043822 | Cyclodecanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D004095 | Dihydropyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
Not provided
Not provided
| Male |
|
| Hispanic Caucasian |
|
| African American |
|
| Asian |
|
| Locally advanced breast cancer |
|
|
|
Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG003 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG004 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG005 | Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG006 | Experimental: Phase II: RP2D Determined in the Phase Ib | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. |
|
|
|
| OG002 | Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 12.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG003 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 15 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 75 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG004 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 17.5 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG005 | Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Phase Ib: L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
| OG006 | Experimental: Phase II: RP2D Determined in the Phase Ib | Phase II: L-NMMA starting dose will be the RP2D determined in the Phase Ib portion of the study. L-NMMA and docetaxel will be given for 6 21-day cycles. L-NMMA at doses of 20 mg/kg will be administered IV on Days 1-5. Docetaxel will be administered at 100 mg/m2 as an IV 15 min after L-NMMA infusion Day 1. |
|
|
| Participants |
|
|
| Units | Counts |
|---|
| Participants |
|
|
|
| Progressive Disease |
|
| Treatment Failure |
|