| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
To evaluate the efficacy of XL184 in subjects with one of the following advanced solid tumors:
a. Breast Cancer
b. Gastric and Gastroesophageal Junction Cancer
c. Hepatocellular Carcinoma (HCC)
d. Melanoma
e. Non-small Cell Lung Cancer
f. Ovarian, primary peritoneal or fallopian tube Carcinoma
g. Pancreatic Cancer
h. Castration-Resistanct Prostate Cancer (CRPC)
i. Small Cell Lung Cancer |
|
| MedDRA Classification |
| 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 this study is:
- To evaluate the efficacy of XL184 in subjects with advanced solid tumors |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
- To evaluate the safety and tolerability of XL184 in subjects with advanced solid tumors
- To correlate the pathway dysfunction of desease-related genes or proteins such as MET and downstream signaling molecules with clinical outcome
- To further characterize the pharmacokinetic (PK) and pharmacodynamic parameters of XL184
To evaluate the safety and efficacy of cabozantinib at two starting dose levels ( 100mg and 39.4 mg once daily (qd))
The exploratory objective of this study is:
- To identify surrogate biomarkers associated with clinical activity |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has a cytologically or histologically and radiologically confirmed, advanced, recurrent, or metastatic solid tumor of the nine types listed below (a i)
The following limitations on prior systemic anticancer treatments apply:
• The maximum number of prior systemic treatment regimens apply to the advanced, recurrent, or metastatic disease state.
• Unless otherwise specified in a-i, determination of the number of prior treatments will be based on the following:
• Prior systemic treatments include standard and investigational chemotherapy and targeted therapies (including targeted biologic therapies).
• Neoadjuvant, adjuvant, hormonal, or locally administered therapy (including embolization, ablation), radiotherapy, and immunotherapy do not count towards these restrictions.
• Retreatment with the same systemic regimen is counted as one regimen.
Specific restrictions to tumor histology and prior systemic anticancer treatment are as follows:
--NOTE: specific conditions apply to all following subsections a to i, please check Protocol- not displayed here due to space restriction-
a. Breast Cancer
b. Gastric and Gastroesophageal Junction Cancer
c. Hepatocellular carcinoma (HCC)
d. Melanoma
e. Non-small cell lung cancer
f. Ovarian, primary peritoneal or fallopian tube carcinoma
g. Pancreatic cancer
h. Castration-Resistant Prostate Cancer (CRPC)
i. Small Cell Lung Cancer
2. The subjects must have evidence of progressive disease (PD) by investigator assessment on CT, MRI, or bone scan:
a. For RDT cohorts: per mRECIST 1.0 (Appendix F).
b. For NRE cohorts: per mRECIST 1.1 (Appendix G); or criteria specified in inclusion criteria #1(v) for CRPC.
c. Newly diagnosed subjects without prior treatment, if allowed per tumor-specific inclusion criterion 1, are exempt from these criteria.
3. Subjects having any tumor type other than CRPC must have at least one lesion that is not within a previously irradiated field and is measurable on CT or MRI scan:
a. For RDT cohorts: per mRECIST 1.0 (Appendix F).
b. For NRE cohorts: per mRECIST 1.1 (Appendix G).
4. The subject has recovered to baseline or CTCAE ≤ Grade 1 from toxicities related to prior treatment, except alopecia, lymphopenia, other non-clinically significant AEs, including AEs attributed to androgen deprivation therapy for CRPC subjects.
5. The subject is ≥ 18 years old on the day of consent.
6. Archival tumor tissue, (unstained sections, paraffin block, or frozen tumor tissue) has been requisitioned for shipment to the central laboratory, unless prohibited by local regulatory bodies including Institutional Review Boards (IRBs). Alternatively, a new tumor sample may be obtained. SCLC subjects, clinically diagnosed HCC subjects, and any subjects diagnosed ≥ 7 years prior to the date of screening with no additional tumor tissue collected in the last 7 years are excluded from this requirement.
7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. The subject has organ and marrow function as described in protocol:
9. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
10. Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 3 months after the last dose of study drug(s).
11. Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, or ovarian suppression or other reasons. |
|
| E.4 | Principal exclusion criteria |
1.The subject has experienced clinically-significant hematemesis or hemoptysis of > 0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
2.The subject has cavitating pulmonary lesion(s) or any lesion abutting or encasing a major blood vessel.
3.The subject has received:
a.Any systemic chemotherapy (including investigational agents) within 4 weeks (with the exception of nitrosoureas/ mitomycin C within 6 weeks), of the first dose of study treatment , OR
b.Biological agents (antibodies, immune modulators, cytokines, or vaccines) within 6 weeks of the first dose of study treatment, OR
c.Hormonal anticancer therapy (not including LHRH agonists or antagonists) within 2 weeks before the first dose of study treatment. For CRPC subjects, specific restrictions on prior hormonal and other anticancer treatments are detailed in inclusion criterion 1h (vi), OR
d.Small-molecular kinase inhibitors or any other type of investigational agent within 4 weeks before the first dose of study treatment or 5 half-lives of the compound or active metabolite, whichever is shorter.
4.The subject has received radiation therapy within 2 weeks of the first dose of study treatment except as follows:
a.Radiation therapy to the thoracic cavity (unless radiation targets bone metastases ), within 3 months.
b.Prior radionuclide treatment within the last 6 months.
5.The subject has initiated treatment with or changed drugs used to control loss of bone mass (eg, bisphosphonates) within 4 weeks prior to the first dose of study treatment.
7.The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results that are above (or 1.3 x) the laboratory upper limit of normal.
8.The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms at screening.
10.The subject has uncontrolled or significant intercurrent illness including, but not limited to, the following conditions:
•Cardiovascular disorders such as symptomatic congestive heart failure (CHF), uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment (blood pressure [BP] must be controlled at screening), unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke (including transient ischemic attack [TIA] or other ischemic event) within 6 months of study treatment, myocardial infarction within 6 months of study treatment, history of thromboembolic event requiring therapeutic anticoagulation within 6 months of study treatment or main portal vein or vena cava thrombosis or occlusion.
•Gastrointestinal disorders such as malabsorption syndrome or gastric outlet obstruction
•Risks for GI perforation or fistula formation, which include intraabdominal
tumor/metastases invading GI tract; active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis or symptomatic cholangitis or appendicitis; history ofabdominal fistula,
GI perforation, bowel obstruction, intra-abdominal abscess, or prior GI
surgery (particularly when associated with delayed or incomplete healing) within 6 months before first dose of study treatment. Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.
•Risk for non-GI fistula formation which includes previous surgical intervention (such as PEG tube placement) and evidence of intraluminal disease involving the trachea or esophagus.
•Other disorders such as infection that is ongoing, or active infection requiring systemic treatment (excluding hepatitis in HCC subjects); serious non-healing wound/ulcer/bone fracture; organ transplant, including liver allografts; clinically significant thyroid dysfunction; history of major surgery within 4 weeks, and minor surgical procedures within 1 week of study treatment; history of significant bleeding within 6 months of study treatment.
11.The subject is unable to swallow capsules.
12.The subject is pregnant or breastfeeding.
13.The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation.
14.The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
15.The subject has had another diagnosis of malignancy, requiring systemic treatment, within the last two years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
Randomized Discontinuation Trial (RDT) Cohorts:
Lead-in Stage:
• Objective Response Rate (ORR) per Modified Response Evaluation Criteria in Solid Tumors mRECIST (version 1.0; Appendix F), per investigator
Randomized Stage:
• Progression-free survival (PFS), per investigator
Non-Randomized Expansion (NRE) Cohorts:
• Castration-resistant Prostate Cancer (CRPC) subjects: Bone scan response per IRF (primary analysis; Section 5.5.11.4) and investigator (supportive analysis; Appendix H)
• Non-CRPC subjects: ORR per mRECIST (version 1.1; Appendix G), per Independent Radiology Facility (IRF) (primary analysis) and investigator (supportive analysis)
|
|
| E.5.2 | Secondary end point(s) |
All tumor type cohorts unless otherwise specified:
• Bone scan response in RDT cohorts, per IRF
ORR (per mRECIST 1.0) in the Randomized Stage, per investigator
• Duration of response, per investigator (all cohorts) and IRF (NRE cohorts)
• PFS (NRE cohorts), per investigator and IRF
• Overall survival (NRE cohorts)
• Changes in tumor markers
CRPC NRE cohorts:
• ORR (per mRECIST 1.1), per IRF and investigator, among subjects with
baseline measurable disease
• Changes in pain and in analgesic medication
• Skeletal-related events (SREs)
• Biomarker and laboratory assessments, including circulating tumor cells
(CTCs), hemoglobin and hematocrit measurements, and markers of bone
metabolism including serum bone-specific alkaline phosphatase (ALP),
CTx (carboxy-terminal collagen crosslinks), and NTx (N-telopeptide
crosslinks)
Safety endpoints include adverse events (AEs) and clinical laboratory parameters. |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 4 |
| 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 | 4 |
| 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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