| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic renal cell carcinoma (RCC), advanced urothelial carcinoma, advanced gastric (including gastro-esophageal [GEJ]) adenocarcinoma, and metastatic colorectal adenocarcinoma (CRC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Kindney cancer, bladder cancer, stomach cancer, colon cancer |
|
| 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 | 10052360 |
| E.1.2 | Term | Colorectal adenocarcinoma |
| 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 | 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) |
|
| 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 | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071114 |
| E.1.2 | Term | Metastatic gastric adenocarcinoma |
| 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 |
Phase 1b:
Primary Objective:
- To determine the recommended Phase 2 dose (RP2D) of ibrutinib in combination with everolimus in RCC, paclitaxel in urothelial carcinoma, docetaxel in gastric adenocarcinoma and cetuximab in CRC.
- To confirm the RP2D of single-agent ibrutinib in UC cohort 5
Phase 2:
Primary Objectives:
- To assess progression-free survival (PFS) of ibrutinib combination therapy in RCC and urothelial carcinoma, and to assess the ORR of ibrutinib combination therapy in gastric adenocarcinoma and CRC, and ibrutinib as a single agent in UC cohort 5 |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
- To assess the overall response rate (ORR) in each cohort
- To assess the safety and tolerability of ibrutinib combination or single agent therapy in each cohort
- To assess the disease control rate (DCR) in each cohort
- To evaluate the pharmacokinetics (PK) of ibrutinib combination therapy in cohorts 1-4
Phase 2:
- To assess the PFS of ibrutinib combination therapy in gastric adenocarcinoma and CRC, and ibrutinib as a single agent in UC cohort 5
- To assess the ORR of ibrutinib combination therapy in RCC and UC cohort 2
- To assess the duration of response (DPR) in each cohort
- To assess the disease control rate (DCR) in each cohort
- To assess the median overall survival (OS) of ibrutinib combination or single-agent therapy in each cohort
- To assess the safety and tolerability of ibrutinib combination or single-agent therapy in each cohort
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed:
- RCC (clear cell)
- Urothelial carcinoma (transitional cell)
- Gastric or GEJ adenocarcinoma
- K-RAS or N-RAS wild-type EGFR expressing CRC
2. One or more measurable lesions per RECIST 1.1 criteria.
3. The following prior criteria should be followed:
- Metastatic RCC: minimum of 1 and maximum of 4 prior regimens, one or more of which must have included a VEGF-TKI
Advanced (locally recurrant and or metastatic) UC: minimum of 1 andmaximum of 2 prior regimens, one of which must have included a platinum based regimen (cohort 2) or a checkpoint inhibitor (cohort 5)
-Advanced (locally recurrent and/or metastatic) urothelial carcinoma: minimum of 1 and maximum of 2 prior regimens, one of which must be a platinum based regimen
- Advanced (locally recurrent and or metastatic) gastric or GEJ adenocarcinoma: minimum of 1 and maximum of 3 prior regimens one of which must be a fluoropyrimidine based regimen
- Metastatic CRC: minimum of 2 and maximum of 4 prior regimens, which must have included both an irinotecan and an oxaliplatin based regimen or unable to tolerate irinotecan chemotherapy
4. Each subject must be assessed by the investigator to be a suitable candidate for treatment with everolimus, docetaxel, paclitaxel, cetuximab or ibrutinib monotherapy, as appropriate according to their type of cancer
5. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of study drug. Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy) are exempt from this criterion
6. Male and female subjects of reproductive potential must agree to perform complete abstinence1 or to use both, a highly effective method of birth control (implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], or sterilized partner) and a barrier method (eg, condoms, cervical rings, cervical condoms, sponge) during the period of therapy and for 90 days after the last dose of ibrutinib, everolimus, docetaxel, and paclitaxel; 6 months after the last dose of cetuximab (6 months for all study drugs in UK only)
7. Adequate hematologic function independent of platelet transfusion and growth factor support for at least 7 days prior to enrollment, with the exception of pegylated G-CSF (granulocyte-colony stimulating factor pegfilgrastim) and darbopoeitin which requires at least 14 days, defined as:
- Absolute neutrophil count >1500 cells/mm3 (1.5 x 10 9/L)
- Platelet count >80,000 cells/mm3 (80 x 10 9/L) for cohorts 1 (RCC)
- Platelet counts >100,000 cells/mm3 (100 x 10 9/L) for cohorts 2 (urothelial carcinoma) and 3 (gastric adenocarcinoma) and 4 (CRC)
- Hemoglobin ≥8.0 g/dL for cohorts 1 (RCC), 2 (urothelial carcinoma), and 3 (gastric adenocarcinoma) • Hemoglobin ≥9.0 g/dL for cohort 4 (CRC)
8. Adequate hepatic and renal function defined as:
- Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤5.0 x upper limit of normal (ULN) if liver metastases, or ≤3 x ULN without liver metastases
- Alkaline phosphatase <3.0 x ULN or ≤5.0 x ULN if liver or bone metastases present
- Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin, such as hemolysis) with the exception of subjects in the gastric adenocarcinoma cohort where docetaxel is administered, these subjects must have bilirubinwithin normal limits (WNL)
- Estimated Creatinine Clearance ≥30 mL/min (Cockcroft-Gault)
9. Men and women ≥18 years of age
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. For subjects with RCC or CRC, an ECOG score of 2 may be acceptable if approved by the medical monitor.
|
|
| E.4 | Principal exclusion criteria |
Disease-Related
1. Anticancer therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 28 days of the first dose of study drug (4 weeks for nitrosureas, mitomycin C, or antibody based therapies)
2. Prior treatment with:
- Everolimus or temsirolimus (RCC cohort)
- Any taxane (urothelial carcinoma cohort 2)
- Any taxane (gastric adenocarcinoma cohort)
- Cetuximab or panitumumab (CRC cohort)
3. Prior radiotherapy to measurable lesion, unless documented
progression has occurred post-irradiation
4. Lack of recovery from previous therapeutic radiation (persistence of Grade ≥2 radiation-related toxicity) or planned radiation therapy during the study period
Concurrent Conditions
5. Any uncontrolled active systemic infection including any infection requiring systemic IV treatment which was completed ≤7 days before Cycle 1 Day 1
6. History of other malignancies, except:
- Malignancy treated with curative intent and with no known active
- disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by investigator
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without current evidence of disease
7. Prior treatment with ibrutinib or other BTK inhibitor 8. ALT and/or AST >1.5 x ULN and alkaline phosphatase >2.5 x ULN (gastric adenocarcinoma cohort only)
9. Known allergy or hypersensitivity to ibrutinib or any other component of combination therapy, including polysorbate 80 or Cremophor® EL (polyoxyethylated castor oil)
10. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE) version 4.03, grade 0 or 1 11. Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia
12. Grade ≥3 sensory peripheral neuropathy
13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
14. Known brain or leptomeningeal disease (CT or MRI scan of the brain required only in case of clinical suspicion of central nervous system involvement)
15. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV) Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
16. Major surgery within 4 weeks of first dose of study drug
17. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk
18. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure, as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment
19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
20. Unable to swallow capsules and/or tablets
21. Concomitant use of warfarin or other Vitamin K antagonists
22. Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix 10)
23. Lactating or pregnant
24. Unwilling or unable to participate in all required study evaluations and procedures
25. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- To assess the median progression-free survival (PFS) in the RCC (cohort 1) and UC Cohort 2
- To assess the ORR in the GC cohort 3, CRC cohort 4, and UC cohort 5. ORR is the proportion of subjects who achieve a CR or PR by RECIST 1.1 criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
A DLRC will review safety data at the completion of the initial Ph 1b portion in each cht to determine the RP2D,prior to continuing with Ph 2.The DLT period will encompass 21 days after the initiation of comb therapy.
Ph 1b will follow a 3+3+3 dose escalation design with 3–9 subjects at each dose level.At each dose level, DLT assessment will be performed in the first 3 subjects.If 1 of 3subjectsexperience a DLT during the first treatment cycle, the dose level will be expanded to 6 subjects.if 2 of 6 have DLT, the dose level will be expanded to 9 subjects.
UC cht 5: the DLT to be confirmed in the first 6 pts; safety data described. For the Ph 1b of cht 5, if 2 subjects within the initial cht of 6 subjects experience a DLT, an additional 3 subjects will be enrolled at the same dose level. |
|
| E.5.2 | Secondary end point(s) |
Secondary End points
- To assess the disease control rate (DCR) will be determined in each cohort. DCR is defined as the proportion of subjects who achieve a best response of CR, PR, SD = 6 weeks in accordance with RECIST 1.1 criteria
- To assess the PFS in the GC (cohort 3), CRC (cohort 4), UC cohort 5
- To assess the ORR in the RCC Cohort 1 and UC cohort 2
- To assess the Overall survival (OS) for each cohort
- To assess the DOR for each cohort
Exploratory End points
- To assess the genes and proteins associated with sensitivity or resistance to ibrutinib (all cohorts)
- To assess the changes in CEA levels (cohort 4 only)
- To assess the correlation of baseline HER-2 expression with response (GC cohort only).
- To assess the pharmacodynamic (PDn) biomarkers (cohorts 1, 2, 3, and 4)
- To assess the PK parameters (all cohorts) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
RCC
-A single interim analysis for futility will take place when the 25th subject dosed at the RP2D level has completed 6 months of follow-up.
Urothelial carcinoma
-A single interim analysis for futility will take place when the 25th subject dosed at the RP2D level has completed 4 months of follow-up.
Gastric adenocarcinoma, CRC and UC cohort 5
-The gastric adenocarcinoma and CRC cohorts employ a Simon´s 2-stage minimax design involving the ORR endpoint. Thus the data supporting proceeding to the second stage will be the best response rate of CR or PR in combination with other safety and efficacy data. |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| integrated protocol design Phase 1b/2 |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| dose escalation/de-escalation |
|
| 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 | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Korea, Republic of |
| Spain |
| United Kingdom |
| 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
|
| A subject will be considered to have completed the study if he or she has died before the end of the study, has not been lost to follow up, or has not withdrawn consent before the end of study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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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