Anaplastic Thyroid Cancer, Differentiated Thyroid Cancer, Thyroid Cancer
Conditions
Keywords
Anaplastic Thyroid Cancer, Thyroid Cancer, Differentiated Thyroid Cancer
Brief summary
This research study is a phase I/II study of MLN0128 in metastatic anaplastic thyroid cancer(ATC) and incurably poorly differentiated or radioidodine refractory differentiated thyroid cancer (DTC). Due to changes in the manufacturing process which resulted in increased absorption of MLN0128 from capsules, a run-in phase I prior to the phase II of the study was needed. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease. MLN0128 prevents tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival. Patients with anaplastic thyroid cancer have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128. Given the activity with everolimus in RAI refractory thyroid cancer, subjects wth metastatic, incurable differentiated RAI refractory and poorly differentiated thyroid cancer were included.
Detailed description
Patients who fulfill eligibility criteria will be entered into the trial to receive MLN0128.
Interventions
DRUGMLN0128
Sponsors
Millennium Pharmaceuticals, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients 18 years or older * Any number of prior chemotherapy or targeted agents including rapamycin analogues allowed * Newly diagnosed or refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination * Must have measurable disease * ECOG performance status 0-2 * No active intracranial metastases * Tissue for correlative studies must be available * Ability to swallow oral medications * Voluntary written consent must be given before performance of any study related procedure * Adequate organ function, as specified below, within 21 days: * Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL; * Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤2.5 x ULN (≤5 x ULN if liver metastases are present); * Renal: creatinine clearance ≥50 mL/min * Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL * Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study) * Female patients who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse * Male patients, even if surgically sterilized (ie, status post-vasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or * Agree to completely abstain from heterosexual intercourse * Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be discontinued
Exclusion criteria
* Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period * Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment * Treatment with any investigational products within 14 days * Failed to recover from the reversible effects of prior anticancer therapies * Manifestations of malabsorption due to prior gastrointestinal surgery or disease * Poorly controlled diabetes mellitus * History of any of the following within the last 6 months prior to study entry: * Ischemic myocardial event * Ischemic cerebrovascular event * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia * Placement of a pacemaker for control of rhythm * New York Heart Association Class III or IV heart failure * Pulmonary embolism * Significant active cardiovascular or pulmonary disease at the time of study entry, including: * Uncontrolled high blood pressure * Pulmonary hypertension * Uncontrolled asthma or O2 saturation \< 90% * Significant valvular disease * Medically significant (symptomatic) bradycardia * History of arrhythmia requiring an implantable cardiac defibrillator * Baseline prolongation of the rate-corrected QT interval (QTc) * Treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) [Phase I Dose Escalation] | cycle 1 (cycle duration=28 days) | The MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D). |
| Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation] | cycle 1 (cycle duration=28 days) | DLT is defined as an adverse event based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications, that meets any of the criteria (hematologic, renal, hepatic, endocrine, metabolic/laboratory, pancreatitis, cardiac, neurotoxicity, mood alteration, dermatologic\] listed in section 5.3.2 of the protocol. |
| 4-month Progression Free Survival (PFS4) Rate - ATC Cohort [Phase II] | Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 4-months. | PFS4 rate is the percentage of participants remaining alive and progression-free at 4-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival (OS) [Phase II] | Long term follow-up for survival was every 3 months post-treatment end up to 24 months. | OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. |
| Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months). | All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Maximum grade toxicity by AE type was then calculated. Incidence is the number of participants experiencing at least one grade 2-5 treatment-related AE during the time of observation. |
| Clinical Benefit (CBR) by BRAF V600E Status [Phase II] | BRAF V600E status per NGS at baseline. Disease response was assessed every 2 cycles on treatment until the first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC). | CBR was defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of CR or PR. SD is neither PR or better nor PD (defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since treatment start, or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions). Participants were classified by BRAF V600E status based on established methods using tumor tissue collected at baseline. |
| BRAF V600E Status [Phase II] | Baseline | Participants were classified by BRAF V600E mutation status evaluated by next generation sequencing (NGS) platforms using tumor tissue collected at baseline. |
| 6-month Progression Free Survival (PFS6) Rate - DTC Cohort [Phase II] | Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 6-months. | PFS6 rate is the percentage of patients remaining alive and progression-free at 6-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions. |
| Overall Response Rate (ORR) [Phase II] | Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC). | ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of objective response. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled from July 2015 to July 2020.
Participants by arm
| Arm | Count |
|---|---|
| P1: DL1 Phase I Dose Level 1 participants received MLN0128 3 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. | 3 |
| PI: DL2 Phase I Dose Level 2 participants received MLN0128 4 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. | 3 |
| PI: DL3 Phase I Dose Level 3 (dose escalation) participants received MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. | 3 |
| P1: DL3 EXP Phase 1 Dose Level 3 participants receive MLN0128 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. | 10 |
| Phase II: ATC Cohort (Including DL3 PI) Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study. | 18 |
| Phase II: DTC Cohort (Including DL3 PI) Phase II participants receive MLN0128 at the maximum tolerated dose/ recommended phase II dose of 5 mg orally, daily for 28 days. Participants are treated until disease progression or withdrawal of consent. Per design, all participants treated at the maximum tolerated dose (DL3) would be enrolled in the PII study. | 22 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1: PI DL1 Dose Escalation | Disease Progression | 3 | 0 | 0 | 0 | 0 | 0 |
| Period 2: PI DL2 Dose Escalation | Death | 0 | 1 | 0 | 0 | 0 | 0 |
| Period 2: PI DL2 Dose Escalation | Disease Progression | 0 | 2 | 0 | 0 | 0 | 0 |
| Period 3: PI DL3 Dose Escalation | Disease Progression | 0 | 0 | 3 | 0 | 0 | 0 |
| Period 4: PI DL3 Dose Expansion | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 4: PI DL3 Dose Expansion | Disease Progression | 0 | 0 | 0 | 5 | 0 | 0 |
| Period 4: PI DL3 Dose Expansion | Intercurrent Illness | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 4: PI DL3 Dose Expansion | Physician Decision | 0 | 0 | 0 | 2 | 0 | 0 |
| Period 4: PI DL3 Dose Expansion | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 5: Phase II | Adverse Event | 0 | 0 | 0 | 0 | 0 | 2 |
| Period 5: Phase II | Disease Progression | 0 | 0 | 0 | 0 | 10 | 11 |
| Period 5: Phase II | Intercurrent Illness | 0 | 0 | 0 | 0 | 2 | 0 |
| Period 5: Phase II | Physician Decision | 0 | 0 | 0 | 0 | 3 | 2 |
| Period 5: Phase II | Still On treatment | 0 | 0 | 0 | 0 | 0 | 3 |
| Period 5: Phase II | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 | 4 |
Baseline characteristics
| Characteristic | P1: DL1 | Total | P1: DL3 EXP | PI: DL3 | PI: DL2 | Phase II: ATC Cohort (Including DL3 PI) | Phase II: DTC Cohort (Including DL3 PI) |
|---|---|---|---|---|---|---|---|
| Age, Continuous Phase I | 59.3 years | 67.7 years | 65.7 years | 55.7 years | 75.8 years | — | — |
| Age, Continuous Phase II | — | 65.5 years | — | — | — | 64.6 years | 66.2 years |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase I ECOG PS0 | 0 Participants | 4 Participants | 3 Participants | 0 Participants | 1 Participants | — | — |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase I ECOG PS1 | 2 Participants | 14 Participants | 7 Participants | 3 Participants | 2 Participants | — | — |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase I ECOG PS2 | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | — | — |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase II ECOG PS0 | — | 5 Participants | — | — | — | 5 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase II ECOG PS1 | — | 33 Participants | — | — | — | 12 Participants | 21 Participants |
| Eastern Cooperative Oncology Group Performance Score (ECOG PS) Phase II ECOG PS2 | — | 2 Participants | — | — | — | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Phase I Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | — | — |
| Ethnicity (NIH/OMB) Phase I Not Hispanic or Latino | 3 Participants | 18 Participants | 10 Participants | 3 Participants | 2 Participants | — | — |
| Ethnicity (NIH/OMB) Phase I Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Phase II Hispanic or Latino | — | 1 Participants | — | — | — | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Phase II Not Hispanic or Latino | — | 39 Participants | — | — | — | 18 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Phase II Unknown or Not Reported | — | 0 Participants | — | — | — | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Phase I Black/African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race/Ethnicity, Customized Phase I Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | — | — |
| Race/Ethnicity, Customized Phase I White | 3 Participants | 18 Participants | 10 Participants | 3 Participants | 2 Participants | — | — |
| Race/Ethnicity, Customized Phase II Black/African American | — | 1 Participants | — | — | — | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Phase II Other | — | 1 Participants | — | — | — | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Phase II White | — | 38 Participants | — | — | — | 17 Participants | 21 Participants |
| Sex: Female, Male Phase I Female | 2 Participants | 9 Participants | 5 Participants | 1 Participants | 1 Participants | — | — |
| Sex: Female, Male Phase I Male | 1 Participants | 10 Participants | 5 Participants | 2 Participants | 2 Participants | — | — |
| Sex: Female, Male Phase II Female | — | 22 Participants | — | — | — | 11 Participants | 11 Participants |
| Sex: Female, Male Phase II Male | — | 18 Participants | — | — | — | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 10 | 0 / 12 | 0 / 15 | 0 / 18 | 0 / 22 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 10 / 10 | 12 / 12 | 15 / 15 | 18 / 18 | 22 / 22 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 0 / 3 | 3 / 10 | 3 / 12 | 6 / 15 | 4 / 18 | 8 / 22 |
Outcome results
Primary
4-month Progression Free Survival (PFS4) Rate - ATC Cohort [Phase II]
PFS4 rate is the percentage of participants remaining alive and progression-free at 4-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
Time frame: Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 4-months.
Population: The analysis dataset is comprised of all participants enrolled to the Phase II ATC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Dose Escalation Participants | 4-month Progression Free Survival (PFS4) Rate - ATC Cohort [Phase II] | 11.1 percentage of participants |
Primary
Maximum Tolerated Dose (MTD) [Phase I Dose Escalation]
The MTD is determined by the number of participants who experience a dose limiting toxicity (DLT). The MTD is defined as the highest dose at which fewer than one-third of participants experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D).
Time frame: cycle 1 (cycle duration=28 days)
Population: The analysis datasets reflects participants who enrolled on the phase I dose escalation study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Dose Escalation Participants | Maximum Tolerated Dose (MTD) [Phase I Dose Escalation] | 5 mg |
Primary
Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation]
DLT is defined as an adverse event based on the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications, that meets any of the criteria (hematologic, renal, hepatic, endocrine, metabolic/laboratory, pancreatitis, cardiac, neurotoxicity, mood alteration, dermatologic\] listed in section 5.3.2 of the protocol.
Time frame: cycle 1 (cycle duration=28 days)
Population: The analysis population is comprised of all participants enrolled in the PI dose escalation design.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase I Dose Escalation Participants | Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation] | 0 Participants |
| Phase I: Dose Level 2 (PI DL2) | Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation] | 0 Participants |
| Phase I: Dose Level 3 (PI DL3) | Number of Participants With Dose Limiting Toxicity (DLT) [Phase I Dose Escalation] | 0 Participants |
Secondary
6-month Progression Free Survival (PFS6) Rate - DTC Cohort [Phase II]
PFS6 rate is the percentage of patients remaining alive and progression-free at 6-months from study entry. Per RECIST 1.1 for target lesions: disease progression (PD) is at least a 20% increase in sum longest diameter (LD), taking as reference the smallest sum on study with at least 5 mm absolute increase or the appearance of one or more new lesions. For non-target lesions, PD is appearance of one or more new lesions or unequivocal progression of existing non-target lesions.
Time frame: Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Relevant for this endpoint was observation at 6-months.
Population: The analysis dataset is comprised of all participants enrolled to the Phase II DTC cohort.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Dose Escalation Participants | 6-month Progression Free Survival (PFS6) Rate - DTC Cohort [Phase II] | 45.5 percentage of participants |
Secondary
BRAF V600E Status [Phase II]
Participants were classified by BRAF V600E mutation status evaluated by next generation sequencing (NGS) platforms using tumor tissue collected at baseline.
Time frame: Baseline
Population: The analysis dataset is comprised of participants with evaluable baseline samples.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Phase I Dose Escalation Participants | BRAF V600E Status [Phase II] | Absent | 7 Participants |
| All Phase I Dose Escalation Participants | BRAF V600E Status [Phase II] | Present | 4 Participants |
| Phase I: Dose Level 2 (PI DL2) | BRAF V600E Status [Phase II] | Absent | 8 Participants |
| Phase I: Dose Level 2 (PI DL2) | BRAF V600E Status [Phase II] | Present | 8 Participants |
Secondary
Clinical Benefit (CBR) by BRAF V600E Status [Phase II]
CBR was defined as the percentage of participants achieving complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of CR or PR. SD is neither PR or better nor PD (defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since treatment start, or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions). Participants were classified by BRAF V600E status based on established methods using tumor tissue collected at baseline.
Time frame: BRAF V600E status per NGS at baseline. Disease response was assessed every 2 cycles on treatment until the first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
Population: The analysis dataset is comprised of participants with evaluable baseline samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Dose Escalation Participants | Clinical Benefit (CBR) by BRAF V600E Status [Phase II] | 25 percentage of participants |
| Phase I: Dose Level 2 (PI DL2) | Clinical Benefit (CBR) by BRAF V600E Status [Phase II] | 28.6 percentage of participants |
| Phase I: Dose Level 3 (PI DL3) | Clinical Benefit (CBR) by BRAF V600E Status [Phase II] | 87.5 percentage of participants |
| PI DL3 Exp | Clinical Benefit (CBR) by BRAF V600E Status [Phase II] | 75.0 percentage of participants |
Secondary
Median Overall Survival (OS) [Phase II]
OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Time frame: Long term follow-up for survival was every 3 months post-treatment end up to 24 months.
Population: The analysis dataset is comprised of all participants enrolled to the Phase II ATC and DTC cohorts.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Phase I Dose Escalation Participants | Median Overall Survival (OS) [Phase II] | 6.1 months |
| Phase I: Dose Level 2 (PI DL2) | Median Overall Survival (OS) [Phase II] | 20.4 months |
Secondary
Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II]
All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Maximum grade toxicity by AE type was then calculated. Incidence is the number of participants experiencing at least one grade 2-5 treatment-related AE during the time of observation.
Time frame: Assessed on treatment at cycles 1 and 2 (days 1 and 15), cycle 3+ on day 1, at the end of treatment and up to 30 days post-treatment. Participants were on treatment up to 21.6 months (median 2.1 months).
Population: The analysis dataset is comprised of all participants enrolled to the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Phase I Dose Escalation Participants | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 0 Participants |
| Phase I: Dose Level 2 (PI DL2) | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 1 Participants |
| Phase I: Dose Level 3 (PI DL3) | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 0 Participants |
| PI DL3 Exp | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 3 Participants |
| Phase II: ATC Cohort | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 4 Participants |
| Phase II: DTC Cohort | Number of Participants With Grade 3-5 Treatment-related Toxicity [Phase I/Phase II] | 8 Participants |
Secondary
Overall Response Rate (ORR) [Phase II]
ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions; PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Confirmatory scan obtained 8 weeks following initial documentation of objective response.
Time frame: Disease was assessed radiologically every 2 cycles/ 8 weeks on treatment until the earliest of first progression, death or 24 months from study entry. Participants were on treatment up to 196 days (PII ATC) and 454 days (PII DTC).
Population: The analysis dataset is comprised of all participants enrolled to the Phase II ATC and DTC cohorts.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase I Dose Escalation Participants | Overall Response Rate (ORR) [Phase II] | 0 percentage of participants |
| Phase I: Dose Level 2 (PI DL2) | Overall Response Rate (ORR) [Phase II] | 1 percentage of participants |