| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic, GPNMB Over-Expressing, Triple-Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple-Negative Breast Cancer (cancer that does not overexpress hormone (ER or PR) or HER2 receptors) |
|
| 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 | 10075566 |
| E.1.2 | Term | Triple negative breast 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 |
| The primary objective of the study is to evaluate the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer as measured by the duration of progression-free survival (PFS). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are:
• To further assess the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer, as assessed by the objective response rate (ORR), duration of response (DOR) and overall survival (OS).
• To further characterize the safety of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer.
• To obtain pharmacokinetic parameters and to explore the relationships between patient-specific measures of exposure and safety and activity parameters |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be included in the study only if they meet all of the following inclusion criteria at the time of randomization:
1. Female or male subjects with metastatic, histologically or cytologically confirmed carcinoma of the breast.
2. Documented progression of disease, based on radiographic, clinical or pathologic assessment showing increased tumor burden or new site(s) of disease during or subsequent to the last anticancer regimen received.
3. Overexpression of GPNMB (≥ 25% of malignant epithelial cells expressing GPNMB, as determined by a central laboratory using IHC methods) in at least one tumor sample obtained in the advanced setting.
4. Triple-negative status determined in a tumor sample obtained in the advanced setting, according to the following criteria:
a. Minimal or no expression of estrogen and progesterone receptors (<10% of cells positive by immunohistochemistry (IHC)). Patients with low hormone receptor expression (ER and/or PR 1-9%) must be deemed appropriate candidates for cytotoxic chemotherapy by the investigator.
b. Minimal or no expression of HER2 (IHC staining of 0 or 1+; ISH single-probe average HER2 copy number < 4.0 signals/cell; or ISH dual-probe HER2/CEP17a ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell). (Wolff, Hammond et al. 2014):
NOTE: laboratory reports will be required to provide quantitative results of sufficient detail to verify the above eligibility for all patients enrolled.
5. 0 to 2 prior chemotherapy-containing regimens for advanced breast cancer. For the purpose of this criterion, a regimen is defined as any combination of therapy, including sequential therapy, received before progression.
6. Prior receipt of anthracycline-containing chemotherapy in any setting, unless anthracycline therapy is not clinically indicated, in the opinion of the treating investigator
7. Prior receipt of taxane-containing chemotherapy, in any setting
8. Age ≥ 18 years
9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 (Appendix 4).
10. Life expectancy of ≥ 3 months
11. Measurable (target) disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) (Appendix 3). Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or anticipated.
12. Resolution of all chemotherapy or radiation-related toxicities ≤ CTCAE v. 4.0 Grade 1 severity, except for alopecia.
13. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) ≥1500/mm3; hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3.
14. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance > 40 mL/min per the Cockcroft and Gault formula (Appendix 5).
15. Adequate liver function as assessed by total bilirubin ≤ 1.5 x upper limit of normal (ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 x ULN (≤ 5.0 x ULN in the case of liver metastases). Patients with known Gilbert’s syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL.
16. Read, understood, and provided written informed consent and, if applicable, HIPAA authorization. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study for any of the following reasons:
1. Progression/recurrence of breast cancer during or within 3 months of completion of neoadjuvant or adjuvant chemotherapy.
2. Investigational therapy within four weeks before planned start of study treatment.
3. Persistent neuropathy > NCI-CTCAE v. 4.0 Grade 1 (at randomization).
4. History of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin. Compounds of similar composition include Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent.
5. Known hypersensitivity to 5-flourouracil, capecitabine or any of its components.
6. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
7. Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months prior to randomization. Continued use of steroids and/or anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable.
8. Subjects unable to provide informed consent and/or unable to comply with the study procedures.
9. Pregnant or breast-feeding women, and women or men who are not willing to use effective contraception during the time from signing of informed consent through two months after the last dose of study treatment. Effective contraception is defined as double barrier contraception (e.g., condom plus spermicide in combination with a female condom, diaphragm, cervical cap, contraceptive sponge or vaginal ring), intra-uterine device (IUD), implants, injectables, combined oral contraceptives, sexual abstinence (total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic abstinence is not acceptable), or sexual intercourse with only a vasectomized partner. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
10. Previously received capecitabine and discontinued due to progressive disease or intolerance; previously received CDX-011 (CR011-vcMMAE; glematumumab vedotin) or other MMAE-containing agents.
11. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary. Note: microscopic examination of urinalysis is required during screening. If urinary infection is suspected, then a negative urine culture is required prior to enrollment.
12. Chronic use of systemic corticosteroids above the physiologic dose (5 mg per day prednisone or equivalent) within 7 days of enrollment, except for premedication.
13. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and congestive heart failure (New York Heart Association class 3 or 4), a history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry.
14. Any underlying medical condition that, in the investigator’s opinion, will make the administration of study treatment (CDX-011 or capecitabine) hazardous to the patient, or would obscure the interpretation of adverse events.
15. Other malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or any other cancer from which the patient has been disease-free for ≥ 5 years. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary end point:
• Duration of progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Under the assumption of exponential distribution for each arm and uniform enrollment over 2 years, and 10% drop out rate (PFS events cannot be observed), 300 patients (200 in the CDX-011 arm and 100 in the capecitabine arm) are needed, and it is anticipated that 203 PFS events will be observed in approximately 26 months from the date the first patient is randomized. |
|
| E.5.2 | Secondary end point(s) |
Secondary end points:
• Objective response rate (ORR)
• Duration of response (DOR)
• Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective response rate (ORR) is defined as the proportion of patients who achieve a best overall response of complete or partial response according to RECIST 1.1. The primary analysis of ORR will be based upon evaluations by the IRC.
Duration of objective response is defined as the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented. The duration of objective response will be summarized descriptively using the Kaplan-Meier method.
Overall survival (OS) is defined as the number of months from randomization to the date of death due to any cause. |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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