| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced solid tumors and first-line metastatic squamous NSCLC; first-line metastatic or locally advanced cholangiocarcinoma, gallbladder cancer, or ampullary cancer (biliary tract cancer); and first-line metastatic or locally advanced transitional cell carcinoma (TCC) of the urinary tract (bladder cancer). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of Lung, bladder cancer, biliary tract cancer, advanced solid tumors. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005003 |
| E.1.2 | Term | Bladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017614 |
| E.1.2 | Term | Gallbladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| In the expansion phase of the study (Part 2), to evaluate the activity of NC-6004 in combination with gemcitabine in patients with first-line Stage IV squamous NSCLC, first-line advanced or metastatic biliary tract cancer, and first-line metastatic or locally advanced bladder cancer compared with historical control as measured by local investigator/radiologist-assessed progression-free survival (PFS), according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate ORR, DCR (DCR = complete response [CR] + partial response [PR] + stable disease [SD]), DOR, PFS, and OS;
- To evaluate therapy-related AEs;
- To evaluate the safety and tolerability of NC-6004 when combined with gemcitabine;
- To evaluate QoL using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30);
- To evaluate acute and delayed symptoms using the MD Anderson Symptom Inventory (MDASI) and a nausea and vomiting patient diary. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide signed written informed consent prior to the initiation of any
study-specific procedures.
2. (Part 2 only) Cohort 1: Have histologically or cytologically confirmed
diagnosis of Stage IV squamous NSCLC and have not received prior
chemotherapy for metastatic disease. Patients with known sensitizing
mutation in the epidermal growth factor receptor (EGFR) gene or
anaplastic lymphoma kinase (ALK) fusion oncogene must have received
at least 1 and up to 2 targeted therapies prior to enrollment.
- A patient with stable, treated brain metastases is eligible, provided
that there is no evidence of progression after treatment and the patient
does not require corticosteroids, or, if the patient requires
corticosteroid, has been receiving a stable dose of corticosteroids for at
least 14 days prior to assignment to treatment.
- Patients whose tumors are known to harbor an exon 19 deletion or
exon 21 L858R EGFR mutation must have had intolerance or have
progressed on at least 1 and up to 2 EGFR tyrosine kinase inhibitors.
- Patients whose tumors are known to harbor an ALK translocation must
have had intolerance or have progressed on at least 1 and up to 2 ALK
inhibitors.
(Part 2 only) Cohort 2: Have histologically or cytologically confirmed
diagnosis of
nonresectable, recurrent, or metastatic biliary tract carcinoma
(intrahepatic or
extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary
carcinoma) and have not received prior systemic anticancer therapy for
advanced or metastatic disease.
(Part 2 only) Cohort 3: Have histologically or cytologically confirmed
diagnosis of
metastatic or locally advanced TCC of the urinary tract (bladder, urethra,
ureter, renal pelvis) (T3b-T4 N0 M0, Tany N1-N3 M0, or Tany Nany M1)
and are not candidates for surgery.
- Patients must not have received prior treatment with systemic
anticancer
therapy for metastatic or locally advanced urinary tract cancer.
- Certain mixed histologies that are predominantly (>50%) TCC are
eligible:
squamous, adenocarcinoma, and undifferentiated. Mixed
undifferentiated histology requires immunohistochemistry consistent
with a TCC origin. Predominantly squamous or neuroendocrine tumors
are excluded.
3. Have measurable disease per RECIST version 1.1.
4. Are males or females aged ≥18 years.
5. Have an ECOG performance status of 0 to 1.
6. Have adequate bone marrow reserve defined as:
- Absolute neutrophil count of at least 1.5 × 109/L,
- Platelet count of at least 100 × 109/L, and
- Hemoglobin level of 10 g/dL (transfusion is allowed to achieve
hemoglobin
level of at least 10 g/dL).
7. Have adequate liver function defined as:
- Total serum bilirubin <1.5 × upper limit of normal (ULN) and
- Alanine transaminase, aspartate transaminase <2.5 × ULN or, in
patients
with documented hepatic metastasis ≤5.0 × ULN.
8. Have adequate renal function defined as a creatinine clearance ≥50 mL/minute (calculated according to the formula of Cockcroft and Gault 1976) or serum creatinine <1.5 mg/dL.
9. Have a negative pregnancy test result at screening (for females of
childbearing potential; not applicable to patients who are unable to
become pregnant, including those with bilateral oophorectomy and/or hysterectomy or postmenopausal [no menses for the previous 12 months]). The test must be performed within 1 week before Day 1 of treatment.
10. Male patients must agree to use a condom during treatment and for 90 days after dosing. Male patients must agree not to donate sperm for 90 days after dosing.
11. For women of childbearing potential*: are willing to follow 1 of the following effective methods of birth control from the time of study entry to 6 months after the last day of treatment:
• Combined (estrogen- and progestogen-containing) hormonal
contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
• Intrauterine devices
• Intrauterine hormone-releasing system
• Vasectomized partner who has received medical assessment of
surgical success
• Bilateral tubal occlusion
• True sexual abstinence**
*Patients not of childbearing potential include those who are surgically sterile or postmenopausal (no menses for the previous 12 months). For
women not currently taking contraceptive methods at screening, low
user-dependency contraceptive methods (eg, implantable progestogen only hormonal contraception, intrauterine device, intrauterine hormonereleasing system, bilateral tubal occlusion, vasectomized partner) are recommended.
**The reliability of sexual abstinence needs to be evaluated in relation
to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
12. Have reasonably recovered from preceding major surgery as judged by the investigator or have had no major surgery within 4 weeks prior to Day 1 treatment. |
|
| E.4 | Principal exclusion criteria |
1. Have received prior platinum therapy in the past 3 months (Part 1) or 6 months in the adjuvant or neoadjuvant setting (Part 2).
2. Have received prior cisplatin and gemcitabine concomitantly within the last 6 months or are refractory to cisplatin and gemcitabine.
3. Are unable to receive platinum-based therapy due to previous toxicity.
4. Have unresolved toxicity from prior radiation, chemotherapy, or other targeted treatment, including investigational treatment, with the exception of alopecia and ≤Grade 1 peripheral neuropathy according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 (National Cancer Institute 2010).
Clinical judgment by the investigator is allowed to determine if Grade 1 fatigue at
screening is residual toxicity from prior treatment or is a symptom of the patient’s general condition or disease. The investigator and Medical Monitor will discuss the eligibility of patients with baseline toxicity
5. Have evidence suggesting pulmonary fibrosis or interstitial pneumonia.
6. Have a history of thrombocytopenia with complications including hemorrhage or bleeding of ≥Grade 2 according to the NCI CTCAE version 4.03 that required medical intervention or have any hemolytic condition or coagulation disorders that would make participation unsafe in the opinion of the investigator.
7. Have known hypersensitivity to platinum compounds or gemcitabine.
8. Have uncontrolled diabetes or have hypertension requiring more than 3 medications for control of hypertension.
9. Are pregnant or breast-feeding.
10. Have signs or symptoms of organ failure, major chronic illnesses other than cancer, or any concomitant medical or social conditions that, in the opinion of the investigator, make it undesirable for the patient to participate in the study or that could jeopardize compliance with the protocol.
11. Have experienced any of the following within the 6-month period prior to screening:
angina pectoris, coronary artery disease or cerebrovascular accident, transient ischemic attack, cardiac failure with known ejection fraction less than 40%, or cardiac arrhythmia requiring medical therapy.
12. Are unwilling or unable to comply with study procedures or are planning to take a vacation for 7 or more consecutive days during the treatment phase of the study without prior consent from the Medical Monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint progression-free survival (PFS), according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. will be continuously updated and compared with the historical PFS from Phase 3 pivotal cisplatin and gemcitabine trials within each cohort. The PFS hazard model will be updated as PFS data accrue. A hazard ratio (HR) for PFS for each cohort versus historical control will be obtained. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival will be defined as the time from first dose of study product until the first date of either disease progression or death due to any cause and will be evaluated for each dose level and for all patients in the FAS. The date of disease progression will be defined as the earliest date of radiological disease progression as assessed by the investigator using RECIST version 1.1 or clinical disease progression. For patients who have not progressed or died at the time of the analysis, censoring will be performed using the date of the last adequate disease assessment. Once 10 PFS events have been observed, interim analyses will be performed every 6 weeks. At each interim and at the final analysis, there are 3 possible outcomes for each cohort. |
|
| E.5.2 | Secondary end point(s) |
The exploratory endpoints of this study include exploratory safety endpoints of the occurrence of AEs and SAEs after 6 cycles of treatment and the following PK endpoints for micellar platinum in plasma and total platinum in plasma and plasma ultrafiltrate calculated for all patients using noncompartmental analysis:
Cmax (maximum concentration)
Tmax (time to maximum concentration)
AUClast (area under the concentration-time curve from time zero to the last quantifiable concentration)
AUC0-τ (area under the concentration-time curve from time zero to the end of the dosing interval)
AUC0-∞ (area under the concentration-time curve from time zero to infinity)
AI (accumulation index)
Vss (volume of distribution at steady-state)
MRT (mean residence time)
λz (terminal elimination phase rate constant)
T½ (terminal half-life)
CL (clearance)
Vz (volume of distribution)
- Safety endpoints:
The safety endpoints for this study are the incidence and severity of AEs and laboratory abnormalities, according to the NCI CTCAE version 4.03, the occurrence of SAEs and treatment discontinuations due to AEs, and nausea severity and vomiting incidence obtained from the patient diary.
- Efficasy analysis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic plasma and plasma ultrafiltrate will be collected at the following times in Part 2 for up to 6 cycles:
• Before the start of the NC-6004 infusion on Day 1
• At the end of NC-6004 infusion
• Before gemcitabine infusion on Day 8
• At End-of-Treatment visit
Adverse events will be evaluated at each visit during every cycle and graded according to the NCI CTCAE.
Disease response assessment will occur every 6 weeks until disease progression.
Quality of life will be assessed before treatment on Day 1 and Day 8 of each cycle and at the End-of-Treatment visit using the EORTC QLQ-C30.
Symptoms will be assessed before treatment on Day 1 and Day 8 of each cycle and at the End-of-Treatment visit using the core MD Anderson Symptom Inventory |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Italy |
| Poland |
| Romania |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The duration of the study for each patient is defined as the time from the date of signed written informed consent through the End-of-Treatment visit or until death.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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