WO2016064649A1

WO2016064649A1 - Therapy for urothelial carcinoma

Info

Publication number: WO2016064649A1
Application number: PCT/US2015/055716
Authority: WO
Inventors: Mark D. RUTSTEIN; Jonathan D. Schwartz; Shande TANG; Richard A. WALGREN
Original assignee: Eli Lilly And Company
Priority date: 2014-10-24
Filing date: 2015-10-15
Publication date: 2016-04-28
Also published as: CA2961295A1; TW201625304A

Abstract

This invention is directed to the field of cancer treatment, and ramucirumab for use in simultaneous, separate or sequential combination with docetaxel to treat patients with urothelial carcinoma, including second-line advanced or metastatic UC, and as a medicament for the treatment of UC.

Description

THERAPY FOR UROTHELIAL CARCINOMA

This invention is directed to the field of cancer treatment. More specifically, the present invention is directed to ramucirumab for use in simultaneous, separate or sequential combination with docetaxel to treat patients with urothelial carcinoma (UC), more specifically, second-line advanced or metastatic UC, and as a medicament for the treatment of UC.

Urothelial carcinoma is also known as urothelial (transitional cell) carcinoma or urothelial carcinoma (transitional cell tumors, or transitional cell tumors of the urothelium), as well as bladder cancer. More than 90% of urothelial tumors originate in the urinary bladder, 8% originate in the renal pelvis, and the remaining 2% originate in the ureter and urethra. (NCCN Clinical Practice Guidelines in Oncology®, Bladder Cancer Version 2. 2014, National Comprehensive Cancer Network®, available from URL: http://www.nccn.org.)

It has been estimated that 74,690 new cases and 15,580 deaths will be reported for bladder cancer in 2014. (American Cancer Society Cancer Facts and Figures 2014. http://www.cancer.org/research cancerfactsstatistics/cancerfactsfigures2014/index.) Previously, the standard of care in first-line treatment of bladder cancer has been methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). However, this treatment regimen has considerable toxicity, and therefore is only used in a highly selected patient population. Cisplatin-gemcitabine combination has replaced MVAC as the standard for first-line treatment of metastatic bladder cancer (Racioppi, M, et al., Urol Int.

2012;88(3):249-258.) Although a significant number of patients have an objective response to first-line therapy, 90% will relapse and have very poor prognosis.

Currently, there are no FDA-approved agents for the treatment of second-line advanced or metastatic UC. Vinflunine is approved in Europe for the treatment of advanced or metastatic TCC of the urothelial tract, though treatment with vinflunine has only shown a non-statistically significant increase in survival (Bellmunt, J., et al., J Clin Oncol. 27(27) :4454-4461 (2009)). Several agents tested in single agent therapy have shown modest activities, with median survival of 5 to 10 months (Y afi, F.A., et al., Current Oncol. 18(l):e25-e34 (2011)). Docetaxel is administered to transitional cell carcinoma patients as a palliative option in the metastatic setting (NCCN 2014), and is accepted by the medical community in the US and Canada for treatment of advanced disease based on evidence from Phase 2 studies.

Combination regimens in the second-line setting have shown similar median survival numbers as compared with single agents; however, with more toxicities.

Ramucirumab for use in simultaneous, separate or sequential combination with docetaxel surprisingly provides an unexpected survival benefit in advanced or metastatic UC patients.

Additionally, ramucirumab for use in simultaneous, separate or sequential combination with docetaxel is unexpectedly effective in treating patients with visceral metastases.

Visceral metastases are metastases to internal organs including the liver, lungs, and body cavities like the pleura and peritoneum. The site of metastasis depends not only on the primary tumor, but also on individual tumor subtype and genetic profile. To date, visceral metastasis has been correlated with poor prognosis. (Bellmunt, J., et al., ESMO Oncology Clinical Practice Guidelines, European Society for Medical Oncology®, Annals of Oncology 25 (Supp. 3):iii40-iii48 (2014), available from URL:

http://www.esmo.org/Guidelines-Practice/Clinical-Practice-Guidelines.) Patients with visceral metastasis generally do not respond favorably to most therapy. (Id.)

However, ramucirumab for use in simultaneous, separate or sequential combination with docetaxel is unexpectedly effective in the treatment of patients both with and without visceral metastasis or metastases. Therefore, ramucirumab for use in simultaneous, separate or sequential combination with docetaxel can be used to treat patients with visceral metastases where other therapies fail.

The present invention is derived from a Phase 2 clinical trial of ramucirumab for use in simultaneous, separate or sequential combination with docetaxel versus docetaxel monotherapy in second-line advanced or metastatic urothelial carcinoma. "An Open- Label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Docetaxel in Combination With Ramucirumab (IMC- 1121 B) Drug Product or IMC- 18F 1 or Without Investigational Therapy as Second-line Therapy in Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma of the Bladder, Urethra, Ureter, or Renal Pelvis Following Disease Progression on First-line Platinum-based Therapy" (the "Study".)

According to the first aspect of the present invention, there is a method of treating urothelial carcinoma in a patient, comprising administering to a patient in need of such treatment an effective amount of ramucirumab in combination with docetaxel.

Another aspect of the invention is ramucirumab for use in simultaneous, separate or sequential combination with docetaxel for the treatment of urothelial carcinoma.

Another aspect of the invention is use of a combination of ramucirumab with docetaxel for the manufacture of a medicament for the treatment of urothelial carcinoma.

Another aspect of the invention is use of ramucirumab in the manufacture of a medicament for the treatment of urothelial carcinoma, wherein ramucirumab is administered simultaneously, separately, or sequentially with docetaxel.

Another aspect of the invention is use of docetaxel in the manufacture of a medicament for the treatment of urothelial carcinoma, wherein docetaxel is administered simultaneously, separately, or sequentially with ramucirumab.

In another preferred aspect of the invention, the carcinoma is bladder carcinoma, urethra carcinoma, ureter carcinoma or renal pelvis carcinoma.

In another preferred aspect of the invention, the carcinoma is transitional cell carcinoma.

In another preferred aspect of the invention, the carcinoma is advanced or metastatic.

In another preferred aspect of the invention, the patient has visceral metastasis. In another preferred aspect of the invention, the patient does not have visceral metastasis.

In another preferred aspect of the invention, ramucirumab is administered on Day 1 (± 3 days) of a 21-day cycle at a dose of 10 mg/kg and docetaxel is administered on Day 1 of a 21-day cycle at a dose of 75 mg/m².

In another preferred aspect of the invention, ramucirumab is administered intravenously and docetaxel is administered intravenously.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient is selected for treatment if the patient has visceral metastasis.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient is selected for treatment if the patient does not have visceral metastasis.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient has visceral metastasis.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient does not have visceral metastasis.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient has visceral metastasis.

Another aspect of the invention is a method of treating urothelial carcinoma in a patient, comprising testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient does not have visceral metastasis.

Another aspect of the invention is the use of ramucirumab in the manufacture of a medicament for the treatment of urothelial carcinoma in a patient, wherein ramucirumab is administered simultaneously, separately, or sequentially with docetaxel.

In another preferred aspect of the invention is the use of ramucirumab, wherein the treatment comprises testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient has visceral metastasis.

In another preferred aspect of the invention is the use of ramucirumab, wherein the treatment comprises testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient does not have visceral metastasis.

Ramucirumab (also known as "IMC-1121B"), CAS registry number 947687-13-0, is a recombinant human monoclonal antibody directed against the vascular endothelial growth factor receptor 2 (VEGFR2 or VEGF receptor-2). As used herein, the term "ramucirumab," refers to an anti-VEGFR2 antibody comprising two heavy chains, each with the amino acid sequence of SEQ ID NO: 1 , and two light chains, each with the amino acid sequence of SEQ ID NO: 2. Ramucirumab and methods of making and using ramucirumab, including for the treatment of neoplastic diseases such as solid and non- solid tumors, are disclosed in WO2003/075840 and all patents granted therefrom.

As used herein, "IMC-18F1" or "icrucumab" refers to a recombinant human monoclonal antibody directed against the vascular endothelial growth factor receptor 1. IMC-18F1 and methods of making and using IMC-18F1 are disclosed in

WO2006/0055809 and all patents granted therefrom.

As used herein, the terms "treating," "treat," or "treatment," refer to restraining, slowing, lessening, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease, or ameliorating clinical symptoms of a condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or disorder, stabilization of a disease or disorder (i.e., where the disease or disorder does not worsen), delay or slowing of the progression of a disease or disorder, amelioration or palliation of the disease or disorder, and remission (whether partial or total) of the disease or disorder, whether detectable or undetectable. Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease. In one embodiment, the present invention can be used as a medicament. As used herein, the term "cancer" refers to or describes the physiological condition in mammals that is typically characterized by unregulated abnormal cell growth. Included in this definition are benign and malignant cancers, advanced and metastatic carcinomas.

Advanced cancers are cancers that have developed to the point where they cannot be safely removed or where a cure or long-term remission is highly unlikely. Cancers become advanced by growing adjacent to structures that prevent their removal or by spreading from where they started, crossing tissue lines, or to other parts of the body such as lymph nodes or other organs. Advanced cancers may be locally advanced, meaning that they have spread outside the organ of the primary site, but have not yet spread to distant sites. Advanced cancers may also be metastatic, meaning that the cancer cells have spread from the site were the cancer started (the primary site) to other more distant parts of the body (secondary sites).

PET, CT, MRI, and tissue biopsies can be used to detect the presence of a tumor or cancer in an organ. A tumor becomes cancer when it is malignant.

In the methods of the present invention, a therapeutically effective amount of ramucirumab of the invention is administered to a mammal or patient in need thereof. Additionally, a pharmaceutical composition of the invention may include a

therapeutically effective amount of ramucirumab.

A "therapeutically effective amount," refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A

therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount for a patient, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific disease or disorder involved; the target site; the degree of the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; other medications

administered; and other relevant circumstances. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

Generally, dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic response). Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy. Dosing schedules will typically range from a single bolus dosage or continuous infusion, to multiple administrations per day (e.g., every 4-6 hours), or as indicated by the treating physician and the patient's condition.

Dosing frequencies of ramucirumab will be determined by the physicians treating the patient and may be given daily, three times per week, weekly, every two weeks, every three weeks, or less often, and more preferably every 21 days.

Dosing amounts of ramucirumab will also be determined by the physicians treating the patient and may fall within customary ranges, more preferably about 10 mg/kg. In some instances, dosage levels of ramucirumab below 10 mg/kg may be adequate, while in other cases, doses higher than 10 mg/kg may be employed with acceptable side effects.

In the present invention, 10 mg/kg of ramucirumab can be administered on Day 1 (± 3 days) of each 21 -day cycle and 75 mg/m² of docetaxel can be administered on Day 1 (± 3 days) of each 21 -day cycle.

The ramucirumab of the invention can be administered prior to or following the administration of docetaxel, more preferably prior to docetaxel.

In the present invention, any suitable method or route can be used to administer ramucirumab; however, intravenous (i.v.) administration is the preferred route. In the present invention, any suitable method or route can be used to administer docetaxel; however, intravenous (i.v.) administration is the preferred route. It should be emphasized, however, that the present invention is not limited to any particular method or route of administration.

The therapeutically effect amount of the treatment of the invention can be measured by various endpoints commonly used in evaluating cancer treatments, including, but not limited to: extending survival (including OS and PFS); resulting in an objective response (including a CR or a PR); tumor regression, tumor weight or size shrinkage, longer time to disease progression, increased duration of survival, longer PFS, improved OS rate, increased duration of response, and improved quality of life and/or improving signs or symptoms of cancer.

As used herein, the term "progressive disease" (PD) refers to the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

PD may be declared on the basis of "unequivocal progression" in cases where the overall tumor burden increases significantly enough to require a change in therapy; in most cases, a modest increase in the size of one or more non-target lesions is not sufficient to qualify

(especially in the presence of SD or PR in target disease).

As used herein, the term "partial response," (PR) refers to at least a 30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter.

As used herein, the term "complete response" (CR) refers to the disappearance of all non-target lesions, the normalization of the tumor marker level (if tumor markers are measured and are initially above the upper limit of normal, those must normalize for a patient to be considered in complete clinical response). All lymph nodes must be < 10 mm (short axis).

As used herein, the term "stable disease" (SD) refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameter since the treatment started.

As used herein, the term "objective response rate" (ORR) is the proportion of all randomized patients who receive any amount of study medication with PR or CR according to RECIST v 1.1 from the start of the treatment until disease

progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).

As used herein, the term "overall survival" (OS) refers to the time from the date of randomization to the date of death from any cause.

As used herein, the term "progression-free survival" (PFS) refers to the patient remaining alive without the cancer progressing or getting worse. In a preferred aspect of the invention, PFS is defined as the time from randomization in the Study until the first radiographic documentation of objective progression as defined by RECIST (Version 1.1), or death from any cause. Patients who die without a reported prior progression will be considered to have progressed on the day of their death. Patients who did not progress or are lost to follow-up will be censored at the day of their last radiographic tumor assessment.

As used herein, the term "disease control rate" (DCR) refers to lack of disease progression and rate thereof. It refers to the group of patients with a best overall response categorized as CR, PR or SD (specifically excluding the patients with PD), wherein the best overall response is the best response recorded from the start of treatment until PD.

As used herein, the term "clinical benefit rate," refers to SD or better at 12 weeks. The tumor response rate of SD or better (i.e. CR+PR+SD) at 12 weeks is defined as the proportion of patients with a response of SD or better, as defined by RECIST 1.1, at 12 weeks following the first dose of study therapy. Patients will be considered "failure" if they die or if radiographic evaluation indicates a response of PD at 12 weeks or before.

As used herein, the term "extending survival" or "prolonged survival" which are used interchangeably herein, is meant as increasing OS or PFS in a treated patient relative to i) an untreated patient, ii) a patient treated with less than all of the anti-tumor agents in a particular combination therapy, or iii) a control treatment protocol. Survival is monitored following the initiation of treatment or following the initial diagnosis of cancer.

As used herein, "ECOG PS" means ECOG Performance Status, wherein grade 0 is fully active, able to carry on all pre-disease performance without restriction; grade 1 is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, .g., light house work, office work; grade 2 is ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; grade 3 is capable of only limited self-care, confined to bed or chair more than 50% of waking hours; grade 4 is completely disabled, cannot carry on any self-care, totally confined to bed or chair; and grade 5 is dead.

Ramucirumab, where used in a patient for the purpose of treatment, is preferably formulated as a pharmaceutical composition. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g. Remington: The Science and Practice of Pharmacy (Gennaro A., et al, eds., 19^m ed., Mack Publishing Co., 1995).

EXAMPLES

The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way. Detailed descriptions of conventional methods, such as those employed in the construction of vectors and plasmids, the insertion of genes encoding polypeptides into such vectors and plasmids, the introduction of plasmids into host cells, and the expression and determination thereof of genes and gene products can be obtained from numerous publications, including Sambrook, J. et al, Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press (1989) and Coligan, J. et al Current Protocols in Immunology, Wiley & Sons, Incorporated (2007).

TABLE 1: Heavy and Light Chain Amino Acid Sequence of Ramucirumab

Heavy Chain SEQ ID Light Chain SEQ

NO. ID NO.

Full MGWSCIILFLVATATGV 1 MGWSCIILFLVATATGV 2

Length HSEVQLVQSGGGLVKPG HSDIQMTQSPSSVSASIG

GSLRLSCAASGFTFSSYS DRVTITCRASQGIDNWL

MNWVRQAPGKGLEWV GWYQQKPGKAPKLLIY

SSISSSSSYIYYADSVKG DASNLDTGVPSRFSGSG

RFTISRDNAKNSLYLQM SGTYFTLTISSLQAEDFA

NSLRAEDTAVYYCARV VYFCQQAKAFPPTFGGG

TDAFDIWGQGTMVTVSS TKVDIKRTVAAPSVFIFP

ASTKGPSVLPLAPSSKST PSDEQLKSGTASWCLL

SGGTAALGCLVKDYFPE NNFYPREAKVQWKVDN

PVTVSWNSGALTSGVHT ALQ SGNSQES VTEQD SK

FPAVLQSSGLYSLSSWT DSTYSLSSTLTLSKADYE

VPSSSLGTQTYICNVNH KHKVYACEVTHQGLSSP

KPSNTKVDKRVEPKSCD VTKSFNRGEC

KTHTCPPCPAPELLGGPS

VFLFPPKPKDTLMISRTP

EVTCVWDVSHEDPEVK

FNWYVDGVEVHNAKTK

PREEQYNSTYRWSVLT

VLHQDWLNGKEYKCKV

SNKALPAPIEKTISKAKG QPREPQVYTLPPSREEM

TKNQVSLTCLVKGFYPS

DIAVEWESNGQPENNYK

TTPPVLDSDGSFFLYSKL

TVDKSRWQQGNVFSCS

VMHEALHNHYTQKSLS

LSPGK

An Open-Label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Docetaxel in Combination With Ramucirumab (IMC-1121B) Drug Product or IMC-18F1 or Without Investigational Therapy as Second-line Therapy in Patients With Locally Advanced or Metastatic Transitional Cell Carcinoma of the Bladder, Urethra, Ureter, or Renal Pelvis Following Disease Progression on First- line Platinum-based Therapy

Study Design:

The study is an Open-Label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Docetaxel in Combination with Ramucirumab (IMC-1121B) Drug Product or IMC-18F1 or without Investigational Therapy as Second-line Therapy in Patients with Locally Advanced or Metastatic Transitional Cell Carcinoma of the Bladder, Urethra, Ureter, or Renal Pelvis Following Disease Progression on First-line Platinum-based Therapy.

Patients who meet all eligibility criteria are randomized in a 1 : 1 : 1 ratio to one of three treatment arms, Arm A, B or C. Arm A patients (n=44) receive docetaxel monotherapy at 75mg/m² on Day 1 (± 3 days) of each 21 -day cycle; Arm B patients (n=46) receive docetaxel at 75mg/m² on Day 1 and ramucirumab DP at 10 mg/kg on Day 1 (± 3 days) of each 21 -day cycle; and Arm C patients (n=49) receive docetaxel at 75mg/m² on Day 1, and IMC-18F1 at 12 mg/kg on Day 1 (± 3 days) and Day 8 (+ 3 days) of each 21 -day cycle. For Arms B and C, ramucirumab DP or IMC-18F1 is administered prior to docetaxel. Randomization is stratified by the absence or presence of visceral metastases (e.g., liver, lung) and receipt of prior antiangiogenic therapy (Y es/No).

Treatment is continued until disease progression, the development of unacceptable toxicity, noncompliance, withdrawal of consent by the patient, or investigator decision.

Ramucirumab DP is a sterile, preservative- free solution for infusion formulated in an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial), and is administered as an intravenous (I.V.) infusion at a dose of 10 mg/kg every 3 weeks (i.e., Day 1 of each 3 -week cycle). The dose of ramucirumab DP is based on the patient's baseline body weight in kilograms. The infusion is delivered over approximately 60 minutes. The infusion rate may not exceed 25 mg/minute. Subsequent doses of ramucirumab DP are recalculated if there is a > 10% change (increase or decrease) in body weight from last dose calculation; subsequent doses may be recalculated if there is a < 10% change (increase or decrease) in body weight from last dose calculation.

IMC-18F1 (icrucumab) drug product is a sterile, preservative-free solution for infusion formulated in an aqueous solution at a concentration of 5 mg/mL (250 mg/50- mL vial), and is administered as an I.V. infusion at a dose of 12 mg/kg on Days 1 and 8 of each 3 -week cycle. The dose of IMC-18F1 is based on the patient's baseline body weight in kilograms. The infusion is delivered over approximately 60 minutes. The infusion rate may not exceed 25 mg/minute. Subsequent doses of IMC-18F1 are recalculated if there is a > 10% change (increase or decrease) in body weight from last dose calculation;

subsequent doses may be recalculated if there is a < 10% change (increase or decrease) in body weight from last dose calculation.

Efficacy Analysis

As per the pre-defined trial criteria, the trial is to end 1 year after the last patient is randomized, and the last patient has discontinued study treatment and completed the 30- day follow-up visit or all ramucirumab- and IMC- 18F1 -related AEs have been followed until resolved, stabilized, returned to baseline, or deemed irreversible. Two interim efficacy analyses are planned. The first is scheduled to be performed when

approximately 50% of the expected number of PFS events (65 events) occurred. Analysis 1 is performed when 75 PFS events occurred. The second is scheduled to be performed when approximately 75% of the expected number of PFS events (98 events) occurred. Analysis 2 is performed when 103 PFS events occurred. There is no pre-defined alpha- spending function for the interim analysis.

The efficacy analysis is performed on the mITT (intent to treat) population: all patients who are randomized in the study and receive any amount of study medication, regardless of their eligibility for the study, are included in the efficacy analysis. Tumor response and progression is evaluated according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1). The Kaplan-Meier method is used to analyze PFS (primary efficacy endpoint) and to estimate the median survival time with a corresponding 80% confidence interval (CI). Ramucirumab DP in combination with docetaxel is separately compared to the docetaxel monotherapy arm using the log-rank test stratified by presence/absence of prior antiangiogenic therapy (Y/N) and visceral metastasis (Y/N). Ties are handled by the Efron method. The hazard ratio of the combination arm is determined as compared to docetaxel monotherapy arm, by the Cox proportional hazards model.

Secondary efficacy endpoints include ORR, OS and DCR. Frequency and percentage are used to summarize best objective response (classified as CR, PR, SD, PD, or NE according to RECIST v 1.1). The ORR for the combination arm is compared to the docetaxel monotherapy arm using the Cochran-Mantel-Haenszel test, adjusting for the stratification variable. The estimate along with 95% CI is provided. OS is evaluated by the Kaplan-Meier method using the stratified log-rank test to compare ramucirumab DP/docetaxel vs docetaxel. A 95% CI is provided for the median OS for each treatment arm. The hazard ratio of each biological treatment arm is determined as compared to docetaxel alone, by stratified Cox proportional hazards model.

The DCR is measured from the time measurement criteria are first met for CR/PR

(whichever is first recorded) until the first date that the criteria for PD is met (taking as a reference for PD the smallest measurement recorded since the treatment started), or death, is objectively documented. Duration of response is assessed using the Kaplan-Meier method and a 95% CI is provided for the median duration of response. Patients who do not relapse are censored at the day of their last objective tumor assessment.

For all efficacy analyses described above there is no type I error adjustment in this study.

Safety analysis:

The safety analysis is performed on the safety population (all randomized patients who receive any quantity of study medication, regardless of their eligibility for the study).

Phase 2 Interim Analysis Results;

PFS; Ramucirumab, in combination with docetaxel, reduced the risk of disease progression at Analysis 2 by 61% (stratified HR = 0.388; 95% CI: 0.222, 0.677), resulting in a 112% longer median time to disease progression in the ramucirumab plus docetaxel arm (22.0 weeks [95% CI: 9.3, 30.0]) than for the docetaxel arm (10.4 weeks [95% CI: 6.7, 16.9]). These results from Analysis 2 are consistent with the results from Analysis 1 where ramucirumab, in combination with docetaxel, reduced the risk of disease progression by 62% (stratified HR = 0.381; 95% CI: 0.197, 0.734), resulting in a 120% longer median time to disease progression in the ramucirumab plus docetaxel arm (22.0 weeks [95% CI: 9.3, 36.1] vs. 10.0 weeks (95% CI: 6.6, 17.0) for the docetaxel arm. The Kaplan-Meier curves for PFS from Analysis 2 show early and sustained separation and are consistent with the Kaplan-Meier curves from Analysis 1. The p-values of the unstratified log-rank tests from Analysis 1 and Analysis 2 are p=0.0028 and p=0.0006, respectively. If an O'Brien and Fleming alpha-spending function had been used to evaluate the significance of the PFS, the results from both Analysis 1 and Analysis 2 would have passed the rejection boundary to declare the early significance of efficacy. Further sub-group interim analysis of PFS was performed based on presence or absence of visceral metastases.

In patients sub-grouped as Yes for visceral metastasis, ramucirumab, in combination with docetaxel arm in Analysis 2, resulted in a longer median time to disease progression of 18.0 weeks (95% CI: 7.1, 47.3) vs. 10.0 weeks (95% CI: 6.3, 13.9) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.455 (95% CI: 0.230, 0.900)

In patients sub-grouped as No for visceral metastasis, ramucirumab, in combination with docetaxel arm in Analysis 2, resulted in a longer median time to disease progression of 24.1 weeks (95% CI: 16.9, 36.3) vs. 14.1 weeks (95% CI: 6.3, 17.9) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.337 (95% CI: 0.139, 0.815). In patients sub-grouped as Yes for visceral metastasis, ramucirumab, in combination with docetaxel arm in Analysis 1, resulted in a longer median time to disease progression of 28.0 weeks (95% CI: 6.3, NE) vs. 9.6 weeks (95% CI: 6.0, 17.0) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.418 (95% CI: 0.177, 0.987).

In patients sub-grouped as No for visceral metastasis, ramucirumab, in combination with docetaxel arm in Analysis 1, resulted in a longer median time to disease progression of 24.1 weeks (95% CI: 16.9, 68.7) vs. 12.3 weeks (95% CI: 5.6, 17.9) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.324 (95% CI: 0.119, 0.884).

The interim analysis in this study not only showed a statistically significant benefit of ramucirumab for use in simultaneous, separate or sequential combination with docetaxel when compared to docetaxel monotherapy, but shows the unexpected benefit of ramucirumab on both populations of patients categorized as with or without visceral metastasis. These results indicate statistically significant improvement in PFS for docetaxel with ramucirumab for use in simultaneous, separate or sequential second line UC versus standard of care.

OS: Ramucirumab, in combination with docetaxel, increased the median survival at Analysis 2 compared to docetaxel alone (48.9 weeks [95% CI: 30.1, 65.9] vs. 33.4 weeks [95% CI: 24.6, 44.4]) with a stratified hazard ratio of 0.775 (95% CI: 0.434, 1.384). This analysis is based on interim data with approximately 43% censoring in the 2 arms combined. The Kaplan-Meier curves for OS demonstrated an early divergence, occurring at approximately 15 weeks from the time of randomization. This apparent separation is sustained until approximately Week 70, based on limited sample size and data maturity at this later observation period. ORR and DoR: Patients treated with ramucirumab plus docetaxel had a higher ORR (CR+PR) than patients treated with docetaxel at Analysis 2 (19.6% [95% CI: 9.4, 33.9] vs. 4.5% [95% CI: 0.6, 15.5]). For the 9 patients in the ramucirumab plus docetaxel arm that responded, 8 patients experienced progressive disease (PD) or death resulting in a median DoR of 22.1 weeks (95% CI: 2.9, 31. For the 2 patients in the docetaxel arm, 1 patient experienced PD or death resulting in a median DoR of 24.4 weeks (95% CI: non- evaluable [NE], NE). Response rate in the ramucirumab plus docetaxel arm vs the docetaxel arm showed disease control rate (CR+PR+SD) in 67.4% (90% CI = 52.0, 80.5) patients and 43.2% (90% CI = 28.3, 59.0) patients respectively. The p-values of the Fisher's Exact test for ORR and DoR are p=0.0502 and p=0.0333, respectively.

Ramucirumab for use in simultaneous, separate or sequential combination with docetaxel provides significant improvement over the current standard of care in UC, and a significant, unexpected benefit in patients with and without visceral metastasis, as both subgroups respond to ramucirumab for use in simultaneous, separate or sequential combination with docetaxel.

Phase 2 Final Analysis Results;

PFS; Ramucirumab, in combination with docetaxel, reduced the risk of disease progression at final data set by 61% (stratified HR = 0.389; 95% CI: 0.235, 0.643), resulting in a 93% longer median time to disease progression in the ramucirumab plus docetaxel arm (5.4 months [95% CI: 3.1, 6.9]) than for the docetaxel arm (2.8 months [95% CI: 1.9, 3.6]). These results from the final analysis are consistent with the results from Analysis 2 where ramucirumab, in combination with docetaxel, reduced the risk of disease progression by 61% (stratified HR = 0.388; 95% CI: 0.222, 0.677), resulting in a 112% longer median time to disease progression in the ramucirumab plus docetaxel arm (22.0 weeks [95% CI: 9.3, 30.0]) than for the docetaxel arm (10.4 weeks [95% CI: 6.7, 16.9]). The Kaplan-Meier curves for PFS from the final analysis show early and sustained separation and are consistent with the Kaplan-Meier curves from Analysis 1 and 2. The p-values of the unstratified log-rank tests from Analysis 1 and final data are p=0.0028 and p=0.0003, respectively. If an O'Brien and Fleming alpha-spending function had been used to evaluate the significance of the PFS, the results from both

Analysis 1 and Analysis 2 would have passed the rejection boundary to declare the early significance of efficacy. Further sub-group final analysis of PFS was performed based on presence or absence of visceral metastases.

In patients sub-grouped as Yes for visceral metastasis, ramucirumab, in combination with docetaxel arm in final analysis, resulted in a longer median time to disease progression of 4.1 months (95% CI: 2.0, 5.8) vs. 2.4 months (95% CI: 1.5, 3.3) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.429 (95% CI: 0.239, 0.770).

In patients sub-grouped as No for visceral metastasis, ramucirumab, in combination with docetaxel arm in final analysis, resulted in a longer median time to disease progression of 8.3 months (95% CI: 3.1, 15.8) vs. 3.7 months (95% CI: 1.4, 5.5) for the docetaxel monotherapy arm. The stratified HR for this analysis was 0.325 (95% CI: 0.127, 0.836).

The final analysis in this study not only showed a statistically significant benefit of ramucirumab for use in simultaneous, separate or sequential combination with docetaxel when compared to docetaxel monotherapy, but shows the unexpected benefit of ramucirumab on both populations of patients categorized as with or without visceral metastasis. These results indicate statistically significant improvement in PFS for docetaxel with ramucirumab for use in simultaneous, separate or sequential second line UC versus standard of care.

OS: Ramucirumab, in combination with docetaxel, increased the median survival at final analysis compared to docetaxel alone (10.4 months [95% CI: 7.0, 15.1] vs. 9.2 months [95% CI: 5.7, 11.7]) with a stratified hazard ratio of 0.733 (95% CI: 0.454, 1.183). This analysis is based on final data with approximately 41.7% (20.0 % Arm A, 21.7% Arm B) censoring in the 2 arms combined. The Kaplan-Meier curves for OS demonstrated an early divergence, occurring at approximately 15 weeks from the time of randomization. This apparent separation is sustained until approximately Week 70, based on limited sample size and data maturity at this later observation period. ORR and DoR: Patients treated with ramucirumab plus docetaxel had a higher ORR (CR+PR) than patients treated with docetaxel at final analysis (23.9% [95% CI: 12.6, 38.8] vs. 8.9% [95% CI: 2.5, 21.2]). For the 11 patients in the ramucirumab plus docetaxel arm that responded, 9 patients experienced progressive disease (PD) or death resulting in a median DoR of 4.6 months (95% CI: 0.7, 7.0). For the 4 patients in the docetaxel arm, 3 patients experienced PD or death resulting in a median DoR of 4.6 months (95% CI: 2.6, 5.6). Response rate in the ramucirumab plus docetaxel arm vs the docetaxel arm showed disease control rate (CR+PR+SD) in 78.3% (90% CI = 63.6, 89.1) patients and 57.8% (90% CI = 42.2, 72.3) patients respectively. The p-values of the Fisher's Exact test for ORR and DoR are p=0.0881 and p=0.0444, respectively.

Claims

WE CLAIM:

1. A method of treating urothelial carcinoma in a patient, comprising administering to a patient in need of such treatment an effective amount of ramucirumab in combination with docetaxel.

2. The method of claim 1, wherein the carcinoma is bladder carcinoma, urethra carcinoma, ureter carcinoma or renal pelvis carcinoma.

3. The method of claim 1 or 2, wherein the carcinoma is transitional cell carcinoma

4. The method of any of claims 1 to 3, wherein the carcinoma is advanced or

metastatic.

5. The method of any of claims 1 to 4, wherein the patient has visceral metastasis.

6. The method of any of claims 1 to 4, wherein the patient does not have visceral metastasis.

7. The method according to any of claims 1 to 6, wherein ramucirumab is

administered on day 1 of a 21-day cycle at a dose of 10 mg/kg and docetaxel is administered on day one of a 21-day cycle at a dose of 75 mg/m².

8. The method of claim 7, wherein ramucirumab is administered intravenously and docetaxel is administered intravenously.

9. Ramucirumab for use in simultaneous, separate or sequential combination with docetaxel for the treatment of urothelial carcinoma.

10. Ramucirumab for use according to claim 9, wherein the carcinoma is bladder carcinoma, urethra carcinoma, ureter carcinoma or renal pelvis carcinoma.

11. Ramucirumab for use according to claim 9 or 10, wherein the carcinoma is

transitional cell carcinoma.

12. Ramucirumab for use according to any of claims 9 to 11, wherein the carcinoma is advanced or metastatic.

13. Ramucirumab for use according to any of claims 9 to 12, wherein the patient has visceral metastasis.

14. Ramucirumab for use according to any of claims 9 to 12, wherein the patient does not have visceral metastasis.

15. A method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient is selected for treatment if the patient has visceral metastasis.

16. A method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient is selected for treatment if the patient does not have visceral metastasis.

17. A method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient has visceral metastasis.

18. A method of treating urothelial carcinoma in a patient, comprising administering an effective amount of ramucirumab in combination with docetaxel to the patient in need thereof, provided that the patient does not have visceral metastasis.

19. A method of treating urothelial carcinoma in a patient, comprising testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient has visceral metastasis.

20. A method of treating urothelial carcinoma in a patient, comprising testing the patient for the presence of visceral metastasis prior to administering ramucirumab in combination with docetaxel, and administering to the patient an effective amount of ramucirumab in combination with docetaxel if the patient does not have visceral metastasis.