Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Dabrafenib · 15 trials · 48 indications
Progression Free Survival (PFS) was defined as the time from the date of randomization to the date of the first documented progression according to RECIST 1.1 based on Blinded Independent Review Committee (BIRC) assessment, or death due to any cause. The primary analysis was conducted after all patients had either completed a minimum of 16 weeks of treatment or discontinued earlier, and following the occurrence of approximately 95 PFS events (Data cut-off date for the primary analysis was 22 January 2025).
The composite rate of pyrexia related events was calculated as the total number of participants experiencing at least one of the three components of the composite endpoint (i.e., grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), divided by the total number of participants treated in the study and multiplied by 100. Pyrexia is defined as fever ≥ 38 °C. Pyrexia events were graded by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 (Death)
Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses.
Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses.
Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.
PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.
OR is defined as the confirmed occurrence of either a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune \[i\]RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria \[RANO\]). In patients with leukaemia, OR will be defined as the occurrence of CR, CRi (CR with incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval.
DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or iRECIST or standard imaging criteria for specific disease e.g. RANO criteria) and, where relevant (e.g. for haematological malignancies), by standard bone marrow response criteria. Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval.
Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR), as per central independent review assessment and according to RECIST 1.1.
Percentage of participants in the LGG cohort with a best overall confirmed Complete Response (CR) or Partial Response (PR) as assessed per RANO criteria by central independent assessment. The 95% confidence intervals (CIs) were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.
Percentage of participants in the HGG cohort with a best overall confirmed CR or PR as assessed per RANO criteria by central independent assessment. The 95% CIs were computed using two-sided exact binomial method. CR: Complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be off steroids or only on physiologic replacement doses. PR: ≥ 50% reduction, compared to baseline, in the sum of products of the perpendicular diameters for all measurable lesions for at least 4 weeks, no progression of nonmeasureable disease, no new lesions, and stable or improved nonenhancing (T2/FLAIR) lesions. Patient must be on a corticosteroid dose not greater than the dose at the time of baseline scan and be stable or improving clinically.
To determine ORR of dabrafenib in combination with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic melanoma. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by the investigator.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response \[CR\], partial response \[PR\]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response \[CR\], partial response \[PR\]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response \[CR\], partial response \[PR\]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (complete response \[CR\], partial response \[PR\]) by investigator assessment as defined by RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (response assessment criteria (CR, PR, and minor response \[MR\]) WHO Grade 1 and 2 Glioma) by investigator assessment as defined by response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
Overall Response Rate (ORR) was defined as the percentage of participants with a tumor response (updated response assessment criteria (CR, PR) WHO Grade 3 and 4 Glioma) by investigator assessment as defined by modified response assessment for neuro-oncology (RANO). Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
Overall Response Rate (ORR) was defined as the percentage of participants with CR +/- minimal residual disease \[MRD\], PR by investigator assessment as defined by the Consensus Resolution Criteria adapted from the National Comprehensive Cancer Network (NCCN) guidelines. Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
Overall Response Rate (ORR) was defined as the percentage of participants with stringent complete response (sCR), CR, PR, very good partial response (VGPR) by investigator assessment as defined by the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma. Specifically, ORR = number of subjects with a confirmed overall response divided by the total number of subjects in the corresponding analysis population.
The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.
ORR was defined as the percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment as per RECIST v1 .1 criteria. Specifically, ORR = (number of subjects with a confirmed best overall response of CR or PR) divided by the total number of subjects in the corresponding analysis population.
The maximum (peak) observed plasma drug concentration after a single dose of dabrafenib
AUClast is the area under the curve calculated to the last quantifiable concentration point after a single dose of dabrafenib
AUCinf is the area under the plasma concentration time curve extrapolated to infinity after a single dose of dabrafenib
Systemic clearance from plasma of dabrafenib after a single dose
The time to reach maximum (peak) concentration of dabrafenib after a single dose
Terminal elimination rate of dabrafenib after a single dose
Elimination half-life of dabrafenib after a single dose
The apparent volume of distribution during the terminal elimination phase of dabrafenib after a single dose
The amount of unchanged dabrafenib excreted in urine after a single dose
Renal clearance of dabrafenib calculated using plasma AUC after a single dose
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. Cmax of dabrafenib was listed and summarized using descriptive statistics.
Venous whole blood samples were collected for activity-based pharmacokinetics characterization. AUC(0-τ) and AUC(0-inf) of dabrafenib were to be listed and summarized using descriptive statistics.
The distribution of adverse events was done via the analysis of frequencies for Adverse Events, Serious Adverse Events and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Only descriptive analysis performed.
Progression Free Survival (PFS) was defined as the time from study treatment start date to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
| Arm | Type | Description |
|---|---|---|
| Dabrafenib plus Trametinib | EXPERIMENTAL | Eligible participants will receive Dabrafenib 150 mg twice a day (BID) and Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor. |
| Dabrafenib Placebo plus Trametinib Placebo | PLACEBO_COMPARATOR | Eligible participants will receive matching placebo for Dabrafenib 150 mg twice a day (BID) and matching placebo for Trametinib 2 mg once a day (QD) until disease progression as per RECIST 1.1 as confirmed by blinded independent review committee (BIRC), unacceptable toxicity, pregnancy, loss of clinical benefit as determined by the investigator, withdrawal of consent, lost to follow-up, death, or study termination by the sponsor. |
| Dabrafenib and trametinib combination therapy | EXPERIMENTAL | Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months. |
| Dabrafenib and trametinib | EXPERIMENTAL | Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. |
| Dabrafenib and trametinib placebos | PLACEBO_COMPARATOR | Subjects received matching placebos orally for 12 months |
| Vemurafenib | ACTIVE_COMPARATOR | BRAF inhibitor |
| Dabrafenib + Trametinib | EXPERIMENTAL | Dabrafenib and Trametinib combination |
| Dabrafenib + Placebo | ACTIVE_COMPARATOR | Dabrafenib and Trametinib placebo |
| Treatment Arm 07: Dabrafenib and Trametinib | EXPERIMENTAL | This dabrafenib and trametinib treatment arm is for adult, paediatric and TYA patients with cancers harbouring BRAF V600 mutations. |
| Dabrafenib in combination with trametinib | EXPERIMENTAL | Dabrafenib 150 mg twice daily, trametinib 2 mg once daily |
| LGG cohort: dabrafenib and trametinib | EXPERIMENTAL | Participants in the LGG cohort randomized to receive dabrafenib (orally, twice daily and dosed based on weight and age) in combination with trametinib (orally, once daily in combination with the first daily dose of dabrafenib and was dosed based on weight) |
| LGG cohort: carboplatin and vincristine | ACTIVE_COMPARATOR | Participants in the LGG cohort randomized to receive active comparator chemotherapy (carboplatin and vincristine). Participants received one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy. |
| HGG cohort: dabrafenib and trametinib | EXPERIMENTAL | Participants in the HGG cohort received dabrafenib (orally, twice daily and dosed based on weight and age) and trametinib (orally, once daily in combination with the first daily dose of dabrafenib and dosed based on weight) |
| Arm 1 | EXPERIMENTAL | All subjects will receive the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone will be administered approximately 12 hours after the morning dose. Subjects will continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure |
| Cohort A | EXPERIMENTAL | Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity. |
| Cohort B | EXPERIMENTAL | Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity |
| Cohort C | EXPERIMENTAL | Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity |
| Cohort D | EXPERIMENTAL | Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity |
| Cohort A (Dabrafenib Monotherapy) | EXPERIMENTAL | Participants received Dabrafenib 150mg BID and continued treatment until disease progression, death, or unacceptable adverse event. Participants receiving and adequately tolerating dabrafenib as a single agent and who continue to meet the inclusion and exclusion criteria had the option to switch to Dabrafenib (150 mg BID) and Trametinib (2 mg once daily) combination treatment within 4 weeks of radiologic disease progression with prior approval from a medical monitor. |
| Cohort B - Double Combination (Dabrafenib+Trametinib) mBRAF V600E | EXPERIMENTAL | Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Cohort C - Double Combination (Dabrafenib+Trametinib) naive mBRAF V600E | EXPERIMENTAL | Participants received Dabrafenib 150 mg BID in combination with Trametinib 2 mg once daily and continued treatment until disease progression, death, or unacceptable adverse event. |
| Group 1 - Normal renal function | EXPERIMENTAL | Subjects with normal renal function defined as GFR ≥ 90 mL/min at baseline and matching to the renal impaired subject based on gender, race, age, and weight. |
| Group 2 - Severe renal function | EXPERIMENTAL | Subjects with severe renal impairment defined as GFR of 15-29 mL/min at baseline. |
| Group 3 - End stage renal disease (ESRD) | EXPERIMENTAL | Subjects with end stage renal disease (ESRD), defined as GFR of \<15 mL/min at baseline. |
| Part 1: Dabrafenib treatment | EXPERIMENTAL | Three subjects will receive a single dose of 3 mg/kg dabrafenib on Day 1 and repeat dose will begin from Day 2, evenly divided in two daily doses. Once all 3 subjects have been fully evaluated for the first 28 days (including Day 15 PK) and no DLTs are observed, a next subject will be enrolled at the next higher dose levels (i.e., dose escalation to 3.75 mg/kg \[+1\] and may be further to 4.5 mg/kg \[+2\] and so on). If all 3 subjects have not been fully evaluated for the first 28 days or 1 DLT occurred, the fourth subject will be enrolled at the same dose level. If 2 or more DLTs are observed, the next subject will be enrolled at the next lower dose level (i.e., de-escalated to 2.25 mg/kg \[-1\] and may be further to 1.5 mg/kg \[-2\]). Similarly, the process is repeated for the fifth and sixth subjects in a cohort. All subjects will receive treatment till end of study. |
| Part 2: Cohort 1 Low-Grade Gliomas with BRAF V600 mutations | EXPERIMENTAL | Subjects with low-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. |
| Part 2: Cohort 2 High-Grade Gliomas with BRAF V600 mutations | EXPERIMENTAL | Subjects with high-grade gliomas with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. |
| Part 2: Cohort 3 LCH with BRAF V600 mutations | EXPERIMENTAL | Subjects with LCH with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. |
| Part 2: Cohort 4 Melanoma and PTC with BRAF V600 mutations | EXPERIMENTAL | Subjects with other tumors with BRAF V600 mutations will receive the single selected final dose (based on MTD and the age of the subjects) from Part 1 on Day 1. Repeat dosing will begin from Day 2, twice daily till end of study. |
| Part 1: Dabrafenib and Panitumumab | EXPERIMENTAL | In Part 1 subjects will be assigned to escalation cohort of the doublet of dabrafenib and panitumumab based on the monotherapy doses of dabrafenib (150 milligrams \[mg\] twice daily) and panitumumab (6 milligrams per kilogram \[mg/kg\] every-2-week \[Q2W\]). Dose escalation will follow a 3+3 dose escalation procedure. If the initial combination dose of dabrafenib and panitumumab in Cohort 1 (starting dose) is not tolerable, lower dose combination(s) may be evaluated. |
| Part 1: Dabrafenib, Trametinib and Panitumumab | EXPERIMENTAL | In Part 1 after the dabrafenib/panitumumab combination dose is defined, subsequent cohorts will evaluate the addition of trametinib based on a panitumumab dose that is one dose level lower than the dabrafenib/panitumumab dose defined in Cohort 1. Trametinib starting at 1.5 mg once daily will be added to the combination of dabrafenib and panitumumab. Dose escalation will follow a 3+3 dose escalation procedure until the full monotherapy doses of all agents are evaluated or the maximum tolerated dose is determined. |
| Part 2: Dabrafenib and panitumumab | EXPERIMENTAL | In Part 2, subjects will be assigned to expansion cohorts at a selected dose of dabrafenib in combination with panitumumab |
| Part 2: Dabrafenib, Trametinib and Panitumumab | EXPERIMENTAL | In Part 2, subjects will be assigned to expansion cohorts at selected dose of trametinib plus dabrafenib in combination with panitumumab. |
| Part 4a: Trametinib and Panitumumab | EXPERIMENTAL | Subject will be administered starting dose of Trametinib 2 mg once daily and Panitumumab 6mg/kg Q2W. If the initial combination dose of trametinib and panitumumab in Cohort 1 (starting dose) is not tolerable, the lower dose combination defined in de-escalation cohorts (Cohort -1A, -1B and/or -1C) may be evaluated. Cohort -1A: Trametinib 1.5 mg once daily and Panitumumab 6 mg/kg Q2W; Cohort -1B: Trametinib 2 mg once daily and Panitumumab 4.8 mg/kg Q2W; Cohort-1C: Trametinib 1.5 mg once daily and Panitumumab 4.8 mg/kg Q2W |
| Part 4b: Trametinib and Panitumumab | EXPERIMENTAL | In Part 4B cohort expansion, subjects will be assigned to expansion cohorts at a selected dose of trametinib in combination with panitumumab. Enrollment in expansion cohorts will be initiated once dose escalation for the trametinib /panitumumab combination has been completed. Subjects with advanced/metastatic CRC with either a BRAF-mutation (Cohort 1E) or who developed secondary resistance to prior anti-EGFR therapy (Cohort 2E). |
| Part 3a: Dabrafenib and Panitumumab | EXPERIMENTAL | Subjects will be randomized to receive dabrafenib plus panitumumab. Dose levels for dabrafenib, and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. |
| Part 3b: Dabrafenib, Trametinib and Panitumumab | EXPERIMENTAL | Subjects will be randomized to receive study treatment as dabrafenib plus trametinib plus panitumumab. Dose levels for dabrafenib, trametinib and panitumumab in Part 3 will be chosen based on emerging PK, PD, and tolerability data from Part 1 and Part 2. |
| Part 3c: Chemotherapy comparator | EXPERIMENTAL | Subjects will be randomized to receive chemotherapy comparator. The chemotherapy comparator will consist of a standard chemotherapy regimen with or without the addition of a biological agent, based on local practice preferences. The available chemotherapy regimens includes 5-fluorouracil-based chemotherapy |
| Name | Type | Description |
|---|---|---|
| Dabrafenib | DRUG | Dabrafenib 150 mg capsule administered orally twice a day (BID) |
| Trametinib | DRUG | Trametinib 2 mg tablet administered once a day (QD) |
| Trametinib Placebo | DRUG | matching placebo tablet for Trametinib 2 mg will be administered orally once a day (QD) |
| Dabrafenib placebo | DRUG | matching placebo capsule for Dabrafenib 150 mg will be administered orally twice a day (BID) |
| Placebos | DRUG | The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment |
| Vemurafenib | DRUG | Vemurafenib 960 mg twice daily orally |
| Carboplatin | DRUG | Carboplatin was supplied locally as commercially available and labelled accordingly to comply with legal requirements of each country. Carboplatin was administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy. Each maintenance cycle was 6 weeks, and consisted of 4 weeks of chemotherapy with 2 weeks of rest. Induction: 175 mg/m\^2 as weekly intravenous (IV) infusion on weeks 1 to 4, and on weeks 7 to 10, on the same day as vincristine dosing Maintenance: 175 mg/m\^2 as weekly IV infusion over 60 minutes on weeks 1 to 4 of each cycle. |
| Vincristine | DRUG | Vincristine was supplied locally as commercially available and labelled accordingly to comply with legal requirements of each country. Vincristine was administered as one course of induction (10 weeks of chemotherapy with 2 weeks of rest), followed by 8 cycles of maintenance chemotherapy. Induction: 1.5 mg/m\^2 as weekly IV bolus infusion (0.05 mg/kg if child is \<12 kg) (maximum dose of 2.0 mg) for 10 weeks. Maintenance: 1.5 mg/m\^2 as weekly IV bolus infusion (0.05 mg/kg if child is \<12 kg) (maximum dose of 2.0 mg) on weeks 1 to 3 of each cycle, on the same day as carboplatin dosing. |
| Panitumumab | DRUG | Panitumumab is a sterile, colorless, translucent-to-white amorphous, proteinaceous powder available as 100 mg panitumumab in 5 mL (20 mg/mL) single-use vial; 200 mg panitumumab in 10 mL (20 mg/mL) single-use vial; 400 mg panitumumab in 20 mL (20 mg/mL) single-use vial; to be administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes. |
| 5-fluorouracil | DEVICE | 5-fluorouracil-based chemotherapy |
Key Inclusion Criteria: * Signed informed consent * Male or female ≥ 18 years of age at time of informed consent * Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid carcinoma * Radioactive-iodine refractory disease * BRAF V600E mutation-positive tumor...