Metastatic Triple Negative Breast Cancer
Conditions
Keywords
breast cancer, nitric oxide synthase, docetaxel, L-NMMA
Brief summary
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.
Detailed description
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.
Interventions
DRUGL-NMMA
Nitric oxide synthase inhibitor
DRUGDocetaxel
Mitotic inhibitor, cytotoxic
DRUGAmlodipine
Long-acting calcium channel blocker
DRUGPegfilgrastim
Colony-stimulating factor
non-steroidal anti-inflammatory drug
Sponsors
The Methodist Hospital Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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 * Age ≥ 18 years * Laboratory values within the following ranges: * 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) * Have adequate organ function (cardiac ejection fraction of ≥ 45%) * Negative serum pregnancy test within 7 days of the administration of the first treatment dose for women of childbearing potential (WOCBP). For WOCBP, adequate contraception must be used throughout the study. * Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments. * Patient must be willing to undergo biopsies as required by the study protocol. Biopsies will be based on acceptable clinical risks as judged by investigator. Tissue from a previous biopsy will be accepted in the form of tissue slides.
Exclusion criteria
History of poorly controlled hypertension (defined as systolic blood pressure \>150 mmHg at baseline) * Patients with metastatic disease who have received radiation therapy, chemotherapy, or non-cytotoxic investigational agents within 2 weeks of study treatment initiation. * Patients who received docetaxel at any line of treatment within the past 12 months * Evidence of New York Heart Association class III or greater cardiac disease * History of myocardial infarction, stroke, ventricular arrhythmia, or symptomatic conduction abnormality within the past 12 months * History of congenital QT prolongation * Absolute corrected QT interval of \>480 msec in the presence of potassium \>4.0 milliequivalent/L and magnesium \>1.8 mg/dL * Any medical or psychiatric condition that would prevent informed consent or limit expected survival to less than 4 weeks * Symptomatic central nervous system metastases * Pregnant or nursing women * Hypersensitivity or intolerance to L-NMMA, docetaxel, amlodipine, pegfilgrastim, or their components * Use of amlodipine or another calcium channel blocker in the past 14 days * Alcoholism or hepatic disease with the exception of liver metastases * Severe renal insufficiency (CrCl \<30 mL/min \[Cockcroft and Gault\]) * History of gastrointestinal bleeding, ulceration, or perforation * Concurrent use of potent cytochrome P450 (CYP)3A4 inhibitors * Concurrent use of potent CYP3A4 inducers * Concurrent use of medications that interact with nitrate/nitrites * Use of an investigational drug within 14 days preceding the first dose of study medication. * Concurrent use of any complementary or alternative medicines * Patients with \> Grade 2 neuropathy * Inability to take aspirin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | 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). | 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. * CR (complete response) = disappearance of all target lesions * PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions * PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions * SD (stable disease) = small changes that do not meet above criteria * Treatment Failure: taken off the study because of adverse events before the first restaging scan after cycle 2 |
| 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. | DLTs assessment window is the duration required for completing one full cycle (through Day 21). | 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. |
| 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. | DLTs assessment window is the duration required for completing one full cycle (through Day 21). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | 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 the time to maximum plasma concentration of the L-NMMA and docetaxel combination. |
| Antitumor Activity | 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). | 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. * CR (complete response) = disappearance of all target lesions * PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions * PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions * SD (stable disease) = small changes that do not meet above criteria * Treatment Failure: taken off the study because of adverse events before the first restaging scan after cycle 2 |
| Dose Limiting Toxicities (DLTs) and Other Adverse Events | 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). | 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. |
| Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21). | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Curve of the L-NMMA and Docetaxel Combination | 18 weeks | Determine the area under the plasma concentration curve of the L-NMMA and docetaxel combination |
| Predictive Biomarkers | 18 weeks | 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 |
Countries
United States
Participant flow
Pre-assignment details
2 subjects withdrew in phase 2 and were in-evaluable.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 2 |
| 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. | 2 |
| 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. | 2 |
| 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 | 2 |
| 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. | 3 |
| 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. | 4 |
| 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. | 20 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 1 | 3 |
| Overall Study | Complete response before the end of 6 cycles | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Overall Study | Physician Decision | 2 | 1 | 2 | 1 | 1 | 2 | 12 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Experimental: L-NMMA 7.5 mg/kg and Docetaxel 75 mg/m2 | Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Experimental: Phase II: RP2D Determined in the Phase Ib |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 58 Years | 51.5 Years | 55 Years | 62 Years | 65 Years | 64 Years | 63 Years | 55 Years |
| Race/Ethnicity, Customized Race African American | 12 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Hispanic Caucasian | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Non-Hispanic Caucasian | 19 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 13 Participants |
| Sex: Female, Male Female | 35 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Stage of Breast Cancer Diagnosis Locally advanced breast cancer | 11 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 10 Participants |
| Stage of Breast Cancer Diagnosis Metastatic breast cancer | 24 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 3 | 0 / 4 | 0 / 20 |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 2 / 2 | 1 / 2 | 3 / 3 | 4 / 4 | 17 / 20 |
| serious Total, serious adverse events | 1 / 2 | 2 / 2 | 0 / 2 | 0 / 2 | 1 / 3 | 1 / 4 | 3 / 20 |
Outcome results
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.
Time frame: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | 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. | 100 mg/m^2 |
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.
Time frame: DLTs assessment window is the duration required for completing one full cycle (through Day 21).
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | 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. | 20 mg/kg |
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. * CR (complete response) = disappearance of all target lesions * PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions * PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions * SD (stable disease) = small changes that do not meet above criteria * Treatment Failure: taken off the study because of adverse events before the first restaging scan after cycle 2
Time frame: 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).
Population: 24 subjects participated in the Phase II portion of the trial
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Metastatic breast cancer | Progressive Disease | 6 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Metastatic breast cancer | Complete Response | 0 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Metastatic breast cancer | Partial Response | 2 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Metastatic breast cancer | Stable Disease | 3 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Metastatic breast cancer | Treatment Failure | 2 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Locally advanced breast cancer | Complete Response | 4 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Locally advanced breast cancer | Partial Response | 5 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Locally advanced breast cancer | Stable Disease | 1 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Locally advanced breast cancer | Progressive Disease | 1 Participants |
| Phase Ib - Dose Finding - L-NMMA | Clinical Benefit Rate | Locally advanced breast cancer | Treatment Failure | 0 Participants |
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. * CR (complete response) = disappearance of all target lesions * PR (partial response) = 30% decrease in the sum of the longest diameter of target lesions * PD (progressive disease) = 20% increase in the sum of the longest diameter of target lesions * SD (stable disease) = small changes that do not meet above criteria * Treatment Failure: taken off the study because of adverse events before the first restaging scan after cycle 2
Time frame: 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).
Population: 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.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Phase Ib - Dose Finding - L-NMMA | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Phase Ib - Dose Finding - L-NMMA | Antitumor Activity | Treatment Failure | 0 Participants |
| Phase Ib - Dose Finding - L-NMMA | Antitumor Activity | Partial Response (<100% reduction) | 0 Participants |
| Phase Ib - Dose Finding - L-NMMA | Antitumor Activity | Progressive Disease (> 20% growth) | 2 Participants |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Treatment Failure | 1 Participants |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Progressive Disease (> 20% growth) | 1 Participants |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Partial Response (<100% reduction) | 0 Participants |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Partial Response (<100% reduction) | 0 Participants |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Treatment Failure | 0 Participants |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Progressive Disease (> 20% growth) | 2 Participants |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Partial Response (<100% reduction) | 1 Participants |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Progressive Disease (> 20% growth) | 1 Participants |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Antitumor Activity | Treatment Failure | 0 Participants |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Treatment Failure | 2 Participants |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Progressive Disease (> 20% growth) | 1 Participants |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Partial Response (<100% reduction) | 0 Participants |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Complete Response (100% reduction) | 0 Participants |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Treatment Failure | 1 Participants |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Progressive Disease (> 20% growth) | 2 Participants |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Partial Response (<100% reduction) | 1 Participants |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Antitumor Activity | Progressive Disease (> 20% growth) | 7 Participants |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Antitumor Activity | Partial Response (<100% reduction) | 7 Participants |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Antitumor Activity | Stable Disease (< 20% change) | 0 Participants |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Antitumor Activity | Complete Response (100% reduction) | 4 Participants |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Antitumor Activity | Treatment Failure | 2 Participants |
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.
Time frame: 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).
Population: Patients who experienced adverse events Grade ≥ 3
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 0 Grade ≥ 3 AE |
| Phase Ib - Dose Finding - L-NMMA | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 12.5 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 15 mg/kg and Docetaxel 75 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 2 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 2 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 17.5 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 1 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 Grade ≥ 3 AE |
| Experimental: L-NMMA 20 mg/kg and Docetaxel 100 mg/m2 | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dehydration | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Elevation of AST/ALT | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Cardiac | 1 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Renal | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Infectious | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Dermatological | 1 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Peripheral neuropathy | 1 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Constitutional | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Vascular | 0 Grade ≥ 3 AE |
| Experimental: Phase II: RP2D Determined in the Phase Ib | Dose Limiting Toxicities (DLTs) and Other Adverse Events | Gastric | 0 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.
Time frame: The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21).
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | 100 mg/m^2 |
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.
Time frame: The Dose Limiting Toxicities (DLT) assessment window is the duration required for completing one full cycle (through Day 21).
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Recommended Phase 2 Dose (RP2D) of the L-NMMA and Docetaxel Combination | 20 mg/kg |
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.
Time frame: 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.
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Phase Ib - Dose Finding - L-NMMA | Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Tmax for LNMMA | 2 Hours |
| Phase Ib - Dose Finding - L-NMMA | Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Tmas for Docetaxel | 4 Hours |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Tmax for LNMMA | 2 Hours |
| Experimental: L-NMMA 10 mg/kg and Docetaxel 75 mg/m2 | Time to Maximum Plasma Concentration of L-NMMA and Docetaxel | Tmas for Docetaxel | 4 Hours |
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
Time frame: 18 weeks
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
Time frame: 18 weeks