Cancer, Solid Tumors
Conditions
Keywords
Metastatic Breast Cancer (MBC), Melanoma, Stomach or Gastroesophageal Junction Carcinoma (GEJ), Hepatocellular Carcinoma (HCC), Small Cell Lung Cancer (SCLC), Non-Small Cell Lung Cancer (NSCLC), Ovarian Cancer, Pancreatic Cancer, Prostate Cancer
Brief summary
This is a Phase 2 study to evaluate the efficacy and safety of cabozantinib (XL184) in subjects with selected advanced tumor types.
Detailed description
The goal of this clinical trial was to learn about the efficacy, safety, and tolerability of cabozantinib against a placebo in subjects with Metastatic Breast Cancer (MBC), Gastric and Gastroesophageal Junction Cancer (GEJ), Hepatocellular Carcinoma (HCC), Melanoma, Non-small Cell Lung Cancer (NSCLC), Ovarian (primary peritoneal or fallopian tube carcinoma), Pancreatic Cancer, Castration-Resistant Prostate Cancer (CRPC), or Small cell Lung Cancer (SCLC) with advanced tumors. The main questions this study aimed to answer were: * What is the efficacy of cabozantinib in subjects with advanced solid tumors? * What is the safety and efficacy of cabozantinib at two starting dose levels 100 milligrams (mg) once daily (po QD) and 39.4 mg po QD? Please note: that the 39.4 mg, po QD was only used in the Non-Randomized Expansion (NRE) part of the study There were three stages to the Randomized Discontinuation Trial (RDT): 1. The Lead in Stage: This stage enrolled eligible patients with advanced solid tumors who received open-label cabozantinib at 100 mg once daily for 12 weeks. 2. The Randomized Stage: Subjects who demonstrated stable disease (SD) at the end of 12 weeks of the Lead-in Stage were randomized to receive cabozantinib or placebo (a look-alike substance that contains no active drug) in a blinded manner. After randomization, when a patient developed progressive disease (PD), study treatments were discontinued and the treatment blind was broken. If the subject was on a placebo, the subject was offered the opportunity to receive cabozantinib. If the subject was already on cabozantinib, the subject entered the Post-Treatment Period where they were followed until death. 3. Open-Label Extension: Subjects who were deemed with partial response (PR) or complete response (CR) at Week 12 of the Lead-In Stage were not randomized but allowed to participate in the Open Label Extension. Patients were given the cabozantinib treatment of 100 mg, po QD. The emerging data supported enrollment in an open-label, Non-Randomized Expansion cohort (NRE). These cohorts targeted patients with prostate and ovarian cancers. For the patients with prostate, they were assigned to either 100 mg, po QD or 39.4 mg, po QD.
Interventions
DRUGCabozantinib
DRUGPlacebo
Sponsors
Exelixis
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The subject has a cytologically or histologically and radiologically confirmed, advanced, recurrent, or metastatic solid tumor of the nine types listed below: * Pancreatic Cancer * Castration-Resistant Prostate Cancer (CRPC) * Hepatocellular Carcinoma (HCC) * Gastric or Gastroesophageal Junction Cancer * Melanoma * Small Cell Lung Cancer (SCLC) * Ovarian cancer, primary peritoneal or fallopian tube carcinoma * Breast cancer that is one of the following subtypes: estrogen receptor positive breast cancer, estrogen receptor/progesterone receptor/HER2-negative (triple-negative), or inflammatory (regardless of receptor status) disease histology * Non-Small Cell Lung Cancer (NSCLC) * Certain requirements for prior therapies may apply * The subject has documented progressive disease at screening * Subjects having any tumor type of 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 * The subject has recovered to baseline or CTCAE ≤ Grade 1 from toxicities related to prior treatment (some exceptions apply) * The subject is ≥ 18 years old on the day of consent * Tissue samples from archival or fresh tissue, or a tissue block of the subject's tumor * The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * The subject has adequate organ function * The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document * Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug(s) * Female subjects of childbearing potential must have a negative pregnancy test at screening
Exclusion criteria
* 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 * The subject has a cavitating pulmonary lesion(s) or a pulmonary lesion abutting or encasing a major blood vessel * Certain restrictions on prior treatments apply * The subject has known symptomatic or uncontrolled brain metastases or epidural disease * The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results that are above (1.3x)the laboratory upper limit of normal * The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and antiplatelet agents (low-dose aspirin (≤81 mg/day), low-dose warfarin (≤1mg/day, and prophylactic low molecular weight heparin (LMWH) are permitted) * The subject has a corrected QT interval(QTcF)\>500 ms at screening * The subject has uncontrolled, significant intercurrent illness * The subject is unable to swallow capsules * The subject is pregnant or breastfeeding * The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation * The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee * 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, or superficial bladder cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | From initial dose through final study visit up to 44 months | Objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.0 per investigator The analysis of ORR in the RDT Cohorts were defined as the proportion of subjects with a best overall response of confirmed complete response (CR) or partial response (PR) per mRECIST 1.0 during the 12-week Lead-In Stage. In the NRE Ovarian Cohort, mRECIST 1.1 was used. ORR for the NRE CRPC Cohorts was not a primary objective and is therefore not captured in the table below. |
| Bone Scan Response (BSR) - NRE, CRPC | From initial dose through final study visit up to 15 months | The reduction of bone scan lesion area (BSLA) by \> 30% was used as the quantitative measure of BSR. BSR was a primary outcome measure for only the NRE CRPC Cohorts. |
| Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | From initial dose through final study visit up to 44 months | Progression Free Survival during the Randomized Stage (Randomized Population) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Objective Response (OR) - Responders From Lead-in Stage | From initial dose through final study visit up to 44 months | Duration of objective response was defined as the time from the tumor assessment that first documented PR or CR that was subsequently confirmed at least 28 days later until the date of documented progression. There were either few or no responders in the Gastric/GEJ, SCLC, and pancreatic cohorts so these cohorts are excluded. |
| Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only | From initial dose through final study visit up to 15 months | — |
| Progression Free Survival (PFS) - Throughout the Study | From initial dose through final study visit up to 44 months | Progression-free survival (PFS) from first dose throughout the study was estimated for all subjects (safety population) using a piecewise method. |
| Duration of Bone Scan Response - NRE Cohorts, CRPC Only | From initial dose through final study visit up to 15 months | The duration of BSR per IRF was calculated for CRPC subjects with an objective response (CR or PR) during the study. |
Countries
Belgium, Israel, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RDT Cohort - CRPC Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 171 |
| RDT Cohort - Melanoma Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 77 |
| RDT Cohort - NSCLC Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 60 |
| RDT Cohort - Pancreatic Cancer Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 20 |
| RDT Cohort - GEJ Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 21 |
| RDT Cohort - HCC Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 41 |
| RDT Cohort - SCLC Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 21 |
| RDT Cohort - Ovarian Cancer Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 70 |
| RDT Cohort - MBC Eligible subjects with advanced solid tumors received open-label cabozantinib at a starting daily dose of 100 mg (freebase weight). | 45 |
| NRE Cohort - CRPC 100 mg Subjects received a single oral daily dose of cabozantinib at 100 mg. | 93 |
| NRE Cohort - CRPC 39.4 mg subjects received a single oral daily dose of cabozantinib at 39.4 mg. | 51 |
| NRE Cohort - Ovarian Cancer 100mg subjects received a single oral daily dose of cabozantinib at 100 mg. | 60 |
| Total | 730 |
Baseline characteristics
| Characteristic | NRE Cohort - CRPC 100 mg | RDT Cohort - Ovarian Cancer | RDT Cohort - MBC | RDT Cohort - NSCLC | NRE Cohort - Ovarian Cancer 100mg | RDT Cohort - GEJ | RDT Cohort - SCLC | RDT Cohort - HCC | RDT Cohort - Melanoma | NRE Cohort - CRPC 39.4 mg | RDT Cohort - Pancreatic Cancer | RDT Cohort - CRPC | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized > 40 - <= 50 years | 3 Participants | 12 Participants | 7 Participants | 3 Participants | 10 Participants | 3 Participants | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 1 Participants | 4 Participants | 59 Participants |
| Age, Customized <= 40 years | 0 Participants | 4 Participants | 6 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 23 Participants |
| Age, Customized > 50 - <= 65 years | 41 Participants | 32 Participants | 26 Participants | 23 Participants | 33 Participants | 9 Participants | 12 Participants | 22 Participants | 28 Participants | 24 Participants | 11 Participants | 60 Participants | 321 Participants |
| Age, Customized > 65 years | 49 Participants | 22 Participants | 6 Participants | 33 Participants | 16 Participants | 8 Participants | 7 Participants | 12 Participants | 38 Participants | 22 Participants | 7 Participants | 107 Participants | 327 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 15 Participants | 2 Participants | 1 Participants | 0 Participants | 12 Participants | 40 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 1 Participants | 6 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 11 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 12 Participants |
| Race (NIH/OMB) White | 85 Participants | 66 Participants | 41 Participants | 51 Participants | 51 Participants | 19 Participants | 18 Participants | 22 Participants | 72 Participants | 45 Participants | 18 Participants | 145 Participants | 633 Participants |
| Sex: Female, Male Female | 0 Participants | 70 Participants | 44 Participants | 27 Participants | 60 Participants | 5 Participants | 12 Participants | 10 Participants | 35 Participants | 0 Participants | 7 Participants | 0 Participants | 270 Participants |
| Sex: Female, Male Male | 93 Participants | 0 Participants | 1 Participants | 33 Participants | 0 Participants | 16 Participants | 9 Participants | 31 Participants | 42 Participants | 51 Participants | 13 Participants | 171 Participants | 460 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 54 / 526 | 53 / 93 | 13 / 51 | 33 / 60 |
| other Total, other adverse events | 524 / 526 | 93 / 93 | 50 / 51 | 59 / 60 |
| serious Total, serious adverse events | 223 / 526 | 53 / 93 | 30 / 51 | 34 / 60 |
Outcome results
Primary
Bone Scan Response (BSR) - NRE, CRPC
The reduction of bone scan lesion area (BSLA) by \> 30% was used as the quantitative measure of BSR. BSR was a primary outcome measure for only the NRE CRPC Cohorts.
Time frame: From initial dose through final study visit up to 15 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Stage - CRPC | Bone Scan Response (BSR) - NRE, CRPC | 74.2 percentage of participants |
| Lead-in Stage - Melanoma | Bone Scan Response (BSR) - NRE, CRPC | 47.1 percentage of participants |
Primary
Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only
Objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.0 per investigator The analysis of ORR in the RDT Cohorts were defined as the proportion of subjects with a best overall response of confirmed complete response (CR) or partial response (PR) per mRECIST 1.0 during the 12-week Lead-In Stage. In the NRE Ovarian Cohort, mRECIST 1.1 was used. ORR for the NRE CRPC Cohorts was not a primary objective and is therefore not captured in the table below.
Time frame: From initial dose through final study visit up to 44 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lead-in Stage - CRPC | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 4.7 percentage of participants |
| Lead-in Stage - Melanoma | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 5.2 percentage of participants |
| Lead-in Stage - NSCLC | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 10 percentage of participants |
| Lead-in Stage - Pancreatic Cancer | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 0 percentage of participants |
| Lead-in Stage - Gastric/GEJ | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 4.8 percentage of participants |
| Lead-in Stage - Hepatocellular Carcinoma | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 4.9 percentage of participants |
| Lead-in Stage - SCLC | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 4.8 percentage of participants |
| Lead-in Stage - Ovarian Cancer | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 21.7 percentage of participants |
| Lead-in Stage - Metastatic Breast Cancer | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 13.6 percentage of participants |
| Lead-in Stage - NRE Ovarian Cancer | Objective Response Rate (ORR) - LEAD IN STAGE, RDT Cohorts and NRE Ovarian Cohort Only | 10.0 percentage of participants |
Primary
Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only
Progression Free Survival during the Randomized Stage (Randomized Population)
Time frame: From initial dose through final study visit up to 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Stage - CRPC | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 5.5 months |
| Lead-in Stage - Melanoma | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.4 months |
| Lead-in Stage - NSCLC | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 4.5 months |
| Lead-in Stage - Pancreatic Cancer | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 2.8 months |
| Lead-in Stage - Gastric/GEJ | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 2.4 months |
| Lead-in Stage - Hepatocellular Carcinoma | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 2.4 months |
| Lead-in Stage - SCLC | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 2.8 months |
| Lead-in Stage - Ovarian Cancer | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | .07 months |
| Lead-in Stage - Metastatic Breast Cancer | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | NA months |
| Lead-in Stage - NRE Ovarian Cancer | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.0 months |
| Randomized Phase - HCC, Cabozantinib Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 2.5 months |
| Randomized Phase - HCC, Placebo Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.4 months |
| Randomized Phase - SCLC, Cabozantinib Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 5.5 months |
| Randomized Phase - SCLC, Placebo Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.5 months |
| Randomized Phase - Ovarian Cancer, Cabozantinib Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 4.9 months |
| Randomized Phase - Ovarian Cancer, Placebo Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.4 months |
| Randomized Phase - MBC, Cabozantinib Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 6.9 months |
| Randomized Phase - MBC, Placebo Arm | Progression-Free Survival (PFS) - Randomized Stage, RDT Cohorts Only | 1.1 months |
Secondary
Duration of Bone Scan Response - NRE Cohorts, CRPC Only
The duration of BSR per IRF was calculated for CRPC subjects with an objective response (CR or PR) during the study.
Time frame: From initial dose through final study visit up to 15 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Stage - CRPC | Duration of Bone Scan Response - NRE Cohorts, CRPC Only | 5.2 months |
| Lead-in Stage - Melanoma | Duration of Bone Scan Response - NRE Cohorts, CRPC Only | NA months |
Secondary
Duration of Objective Response (OR) - Responders From Lead-in Stage
Duration of objective response was defined as the time from the tumor assessment that first documented PR or CR that was subsequently confirmed at least 28 days later until the date of documented progression. There were either few or no responders in the Gastric/GEJ, SCLC, and pancreatic cohorts so these cohorts are excluded.
Time frame: From initial dose through final study visit up to 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Stage - CRPC | Duration of Objective Response (OR) - Responders From Lead-in Stage | 5.59 Months |
| Lead-in Stage - Melanoma | Duration of Objective Response (OR) - Responders From Lead-in Stage | 5.55 Months |
| Lead-in Stage - NSCLC | Duration of Objective Response (OR) - Responders From Lead-in Stage | 6.90 Months |
| Lead-in Stage - Pancreatic Cancer | Duration of Objective Response (OR) - Responders From Lead-in Stage | 4.21 Months |
| Lead-in Stage - Gastric/GEJ | Duration of Objective Response (OR) - Responders From Lead-in Stage | 11.24 Months |
| Lead-in Stage - Hepatocellular Carcinoma | Duration of Objective Response (OR) - Responders From Lead-in Stage | 3.29 Months |
Secondary
Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only
Time frame: From initial dose through final study visit up to 15 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Stage - CRPC | Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only | 11.1 months |
| Lead-in Stage - Melanoma | Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only | 8.0 months |
| Lead-in Stage - NSCLC | Overall Survival (OS) - NRE Cohorts, CRPC and Ovarian Only | 8.5 months |
Secondary
Progression Free Survival (PFS) - Throughout the Study
Progression-free survival (PFS) from first dose throughout the study was estimated for all subjects (safety population) using a piecewise method.
Time frame: From initial dose through final study visit up to 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lead-in Stage - CRPC | Progression Free Survival (PFS) - Throughout the Study | 6.8 months |
| Lead-in Stage - Melanoma | Progression Free Survival (PFS) - Throughout the Study | 2.8 months |
| Lead-in Stage - NSCLC | Progression Free Survival (PFS) - Throughout the Study | 4.0 months |
| Lead-in Stage - Pancreatic Cancer | Progression Free Survival (PFS) - Throughout the Study | 2.7 months |
| Lead-in Stage - Gastric/GEJ | Progression Free Survival (PFS) - Throughout the Study | 1.4 months |
| Lead-in Stage - Hepatocellular Carcinoma | Progression Free Survival (PFS) - Throughout the Study | 5.2 months |
| Lead-in Stage - SCLC | Progression Free Survival (PFS) - Throughout the Study | 3.4 months |
| Lead-in Stage - Ovarian Cancer | Progression Free Survival (PFS) - Throughout the Study | 5.5 months |
| Lead-in Stage - Metastatic Breast Cancer | Progression Free Survival (PFS) - Throughout the Study | 4.3 months |