| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced or Metastatic previously treated non-small cell lung cancer or treatment naïve cisplatin-ineligible urothelial cancer.
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| E.1.1.1 | Medical condition in easily understood language |
Advanced or metastatic previously treated non-small cell lung cancer or treatment naive cisplatin-ineligible urothelial cancer
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| 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 | 20.0 |
| 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) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
To evaluate the Objective Response Rate (ORR) based on Investigator assessment, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of avelumab in combination with axitinib in patients with advanced or metastatic NSCLC who have received at least one prior platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their advanced disease.
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| E.2.2 | Secondary objectives of the trial |
To evaluate the following in patients with advanced or metastatic NSCLC who have received at least one prior platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their advanced disease:
-The safety and tolerability of avelumab in combination with axitinib;
-The anti-tumor activity of avelumab in combination with axitinib;
-The pharmacokinetics of avelumab and axitinib when administered in combination;
-Candidate predictive and/or early response biomarkers in pre-treatment tumor tissue and pre-and post-treatment blood samples that may aid in the identification of a patient subpopulation most likely to benefit from treatment with avelumab in combination with axitinib. Assessments may include but are not limited to tumor mutational burden, immune repertoire and PD-L1 expression within the tumor microenvironment;
-The immunogenicity of avelumab when combined with axitinib.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Diagnosis:
a. NSCLC Cohort: Histologically or cytologically confirmed diagnosis of NSCLC that is locally advanced or metastatic:
-No activating EGFR mutations, Anaplastic lymphoma kinase (ALK) translocations/rearrangements, or c-ros oncogene 1 (ROS1) translocations/rearrangements where testing is standard of care.
-Have received at least 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic NSCLC.
-No more than 2 prior lines of systemic therapy for locally advanced or metastatic disease.
-If disease progression occurred during or within 6 months after neoadjuvant/adjuvant chemotherapy or radiotherapy chemotherapy, the regimen is counted as 1 prior treatment regimen towards the allowed limit of prior treatment regimens.
-Checkpoint inhibitor naïve.
b. UC Cohort: Histologically or cytologically confirmed diagnosis of transitional cell carcinoma (TCC) of the urothelium (if mixed, more than 50% TCC component) including bladder, urethra, ureters, or renal pelvis that is locally
advanced or metastatic:
-No prior systemic treatment for locally advanced or metastatic disease. Prior neoadjuvant or adjuvant therapy is permitted if disease progression occurred >12 months after the completion of therapy.
-Checkpoint inhibitor naïve.
-Ineligible for receiving cisplatin-containing front-line chemotherapy based at least one of the following criteria:
i. ECOG performance status (PS) 2;
ii. Renal dysfunction (defined as creatinine-clearance <60 ml/min);
iii. Grade 2 peripheral neuropathy;
iv. Grade 2 hearing loss (hearing loss measured by audiometry of 25 decibels at two contiguous frequencies)
2. Measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not previously been irradiated.
3. Availability of an archival formalin-fixed and paraffin-embedded (FFPE) tumor tissue block from primary diagnosis specimen or metastatic specimen (if available). If a FFPE tissue block cannot be provided, then 15 unstained slides (10 minimum) will be acceptable. If such an archived sample is not available, a de novo (ie, fresh) tumor sample must be obtained prior to study enrolment.
4. ECOG PS: 0 or 1. For UC patients, ECOG PS 2 is permitted as part of cisplatin-ineligibility criteria.
5. Age 18 years.
6. Estimated life expectancy of at least 90 days.
7. Adequate hepatic function defined by:
a. Total serum bilirubin 1.5 × the upper limit of normal range (ULN);
b. AST and ALT 2.5 × ULN; for subjects with documented metastatic disease to the liver, AST and ALT levels 5 × ULN.
8. Adequate bone marrow function including:
a. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109 /L;
b. Platelets 100,000/mm3 or 100 x 109 /L;
c. Hemoglobin 9 g/dL (5.6 mmol/L) (may have been transfused).
9. Adequate renal function defined by:
a. Estimated creatinine clearance 30 mL/min as calculated using the Cockcroft-Gault (CG) equation.
b. Urinary protein <2+ by urine dipstick. If dipstick is 2+, then 24-hour urinary protein <2 g per 24 hours.
10. Left ventricular ejection fraction (LVEF) lower limit of normal (LLN) as assessed by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO).
11. No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be 140 mm Hg, and the baseline diastolic blood pressure readings must be 90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
12. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
14. Female patients of childbearing potential must have negative serum pregnancy or urine pregnancy test at screening. Female patients of non-childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential |
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| E.4 | Principal exclusion criteria |
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-glucocorticoid induced tumor necrosis factor (TNF) receptor (GITR), anti-lymphocyte activation gene-3 (LAG-3), anti-T cell immunoglobulin and mucin (TIM-3) domain, or anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (including ipilimumab).
2. Prior treatment with an anti-VEGF pathway TKI; prior use of anti-VEGF pathway mAb is permitted.
3. Patients with newly diagnosed brain metastases or known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued corticosteroid treatment for these metastases for at least 14 days prior to study enrollment, and are neurologically stable.
4. Diagnosis of any other malignancy within 5 years prior to study enrollment. Adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason 6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration) are
allowed.
5. Radiologically documented evidence of major blood vessel invasion or encasement by cancer (ie, invasion into the fat plane between the vessel wall and tumor) or intratumor cavitation, regardless of tumor histology.
6. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b. Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions.
7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo-or hyperthyroid disease not requiring immunosuppressive treatment are
eligible.
8. Prior organ transplantation including allogenic stem-cell transplantation.
9. Active infection requiring systemic therapy.
10. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
12. Administration of a live vaccine within 28 days prior to study enrollment.
13. Known prior severe hypersensitivity to the investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade 3).
14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a safety risk based on Investigator's judgment are acceptable. For UC patients, Grade 2 peripheral neuropathy is permitted as part of cisplatin-ineligibility criteria.
15. NCI CTCAE Grade 3 hemorrhage within 28 days prior to study enrollment.
16. Hemoptysis (1/2 teaspoon of bright red blood episode with cough) within 28 days prior to enrolment.
17. Evidence of inadequate wound healing.
18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to enrollment.
19. Any of the following in the previous 6 months prior to study enrollment: deep vein thrombosis or symptomatic pulmonary embolism.
20. Any of the following within the 12 months prior to study enrollment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant
pericardial effusion, cerebrovascular accident, transient ischemic attack.
21. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2 or prolongation of the QTc interval to >500 msec.
22. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart.
23. Spinal cord compression unless the patient has good pain control attained through therapy, and there is stabilization or recovery of neurological function for the 4 weeks prior to first dose of study drug.
24. Known history of immune-mediated colitis, inflammatory bowel disease, immune-mediated pneumonitis, pulmonary fibrosis.
For Exclusion criteria 25 to 33 please see the protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed Objective Response (OR) based on Investigator assessment per RECIST v1.1 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Adverse events (AEs) as characterized by type, severity as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.03, timing, seriousness, and relationship to study treatments;
Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing;
Time-to-event endpoints including time to tumor response (TTR), duration of response (DR), progression-free survival (PFS) based on Investigator assessment per RECIST v1.1, and overall survival (OS);
Pharmacokinetic parameters including trough and maximum concentrations (Ctrough, Cmax) of avelumab and axitinib;
Tumor tissue biomarker status (ie, positive or negative based on, for example, PD-L1 expression and/or quantitation of tumor mutational burden as well as characterization of the immune repertoire in peripheral blood and/or tumor);
Anti-drug antibody (ADA) titers and neutralizing antibodies (NAb) against avelumab.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 20 |
| 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 |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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