Approval Probability
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Adjusted LOA
ML Risk
Label indication ERIVEDGE is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation. FDA label
Also known as GDC-0449 oral capsules (non-labeled), Hedgehog Pathway Inhibitor, Vismodegib, Erivedge, RO5450815
GDC-0449 · 12 trials · 7 indications
The total number of clinically evident basal cell carcinomas = the total number of target and/or non-target lesions present in individual participants.
Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival.
Reasons for "other" included "unknown," "natural causes," "cardiac decompensation," "general state alteration," "deterioration of general state," "clinical deterioration taking into consideration patient's age," "old age," and "disease progression of mediastinal squamous cell carcinoma (SCC)."
Duration on treatment was the number of days between first and last dose of study treatment.
Dose intensity was defined as the percentage of actual number of doses received versus planned.
Complete histologic clearance was defined as the absence of histological evidence of basal cell carcinoma at the target tumor site. Histological examination was performed by an independent pathologist on specimens collected within 2 weeks of the end of treatment period, ie, at 12 weeks after Baseline in Cohort 1, at 36 weeks after Baseline in Cohort 2, and at 20 weeks after Baseline in Cohort 3.
OR=complete (CR) or partial response (PR). Metastatic-CR:Disappearance of all targets. PR:≥30% decreased sum of longest diameter (SLD) of targets compared to baseline (B). Locally advanced-Response=No progressive disease (PD) and ≥30% decreased SLD from baseline (radiography \[R\]) or ≥30% decreased SLD from B (externally visible dimension \[EVD\]) or completely resolved ulceration. CR:Response with no residual BCC on tumor biopsy (otherwise response was PR). PD:Any of ≥20% increased SLD from nadir (R or EVD), new ulceration, new lesions (R or physical exam) or non-target lesion progression by R.
PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Since patients were in remission at the start of the study, they had no evidence of the presence of tumors. Disease progression was defined as radiographic evidence of a tumor. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.
Determined by an Independent Review Committee (IRC) Using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Revised Response Criteria
Maximum observed plasma Concentration (Cmax) \& Concentration at steady-state (Css) following multiple doses of vismodegib (150 mg QD) were analyzed. At steady state the amount of drug administered (in a given time period) is equal to the amount of drug eliminated. Blood samples for assessing Cmax and Css for analysis were collected following multiple oral doses of vismodegib at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8. From the plasma concentration-time curve, the PK parameter Cmax and Css were determined by standard non-compartmental analysis using WinNonlin
The steady state pharmacokinetic profile following oral administration of multiple doses of vismodegib included determining the area under the curve over the dosing interval (AUC\[0-24 hours\]). The AUC\[0-24 hrs\]) was determined by standard non-compartmental analysis using WinNonlin. Blood samples were collected at pre-dose and at 0.5, 1, 2, 4, 8 and 24 hours post-dose on Day 8 to estimate AUC(0-24 hrs).
On Days 1 and 8, blood samples were taken prior to the administration of rosiglitazone and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of rosiglitazone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma rosiglitazone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratio of AUC(0-inf) of rosiglitazone was defined as the AUC(0-inf) of rosiglitazone on Day 8/AUC(0-inf) of rosiglitazone on Day 1.
On Days 1 and 8, blood samples were taken prior to the administration of rosiglitazone and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of rosiglitazone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma rosiglitazone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratio of Cmax of rosiglitazone was defined as the Cmax of rosiglitazone on Day 8/ Cmax of rosiglitazone on Day 1.
On Days 1 and 8, blood samples were taken prior to the administration of the contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of ethinyl estradiol and norethindrone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma ethinyl estradiol and norethindrone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratios of AUC(0-inf) of ethinyl estradiol and norethindrone were defined as the ratios of AUC(0-inf) of ethinyl estradiol and norethindrone on Day 8 divided by AUC(0-inf) of ethinyl estradiol and norethindrone on Day 1, respectively.
On Days 1 and 8, blood samples were taken prior to the administration of the contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) and 30 minutes, and 1, 2, 3, 4, and 6 hours, between 8 and 12 hours, and 24 hours post-dose. Plasma concentrations of ethinyl estradiol and norethindrone were determined using a validated liquid chromatography mass spectrometry/mass spectrometry (LC MS/MS) assay. Individual and mean plasma ethinyl estradiol and norethindrone concentration versus time data were tabulated and plotted by analyte. The pharmacokinetic parameters of each analyte were calculated using standard non-compartmental methods (WinNonlin version 5.2.1, Pharsight Corp., Mountain View, CA). The geometric mean ratios of Cmax of ethinyl estradiol and norethindrone were defined as the ratios of Cmax of ethinyl estradiol and norethindrone on Day 8 divided by Cmax of ethinyl estradiol and norethindrone on Day 1, respectively.
Percent change = (\[trough concentration on Day 15 minus trough concentration on Day 57\] divided by trough concentration on Day 15) multiplied by 100.
Ratio = trough concentration on Day 57 divided by trough concentration on Day 15. If the ratio of total and unbound trough GDC-0449 concentration between Day 57 to Day 15 is less than 1, then it indicates reduction in total and unbound trough GDC-0449 concentration between Day 15 to Day 57.
Plasma GDC-0449 concentrations were reported in nanogram per milliliter (ng/mL) units and converted to micromolar (mcM) units using the molecular weight (421.30 grams per mole \[g/mol\]) prior to PK analysis. Css was calculated for Days 28 to 56.
Plasma GDC-0449 concentrations were reported in ng/mL units and converted to mcM units using the molecular weight (421.30 g/mol) prior to PK analysis.
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). Below the limit of quantitation (BLQ) values at pre-dose were considered as zero for PK analysis.
AUC values were calculated using the linear trapezoidal method when the concentrations were rising and using the logarithmic trapezoidal method when the concentrations were declining (linear up/log down rule in WinNonlin). BLQ values at pre-dose were considered as zero for PK analysis.
A DLT was defined as any Grade 3 or 4 hematologic or major organ toxicity as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) that occurred during the first 35 days after the initiation of study drug (Days 1-35) and was attributable to GDC-0449.
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and pharmacodynamic (PD) data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
Cmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
Tmax was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
Steady state GDC-0449 plasma concentrations (Css) were calculated as an average of plasma concentrations from Study Day 21 (Stage 2) or Study Day 28 (Stage 1) onward.
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Phase I comprised of two stages, a dose-escalation stage with the goal of estimating the maximum tolerated dose (Stage 1), and an expanded cohort to collect additional safety, PK, and PD data at the proposed Phase II dose (Stage 2). Phase II represented the additional cohort initiated with 150 mg hard gelatin capsule identified from the safety, PK and PD data from Stage 1 of the trial.
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
AI was calculated using the formula \[AI = AUC(0-24) on Day 15/AUC(0-24) on Day 1\]. AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AI was estimated if there were extensive PK sampling in more that 50% of the participants to form a curve.
| Arm | Type | Description |
|---|---|---|
| Vismodegib Intermittent Schedule | EXPERIMENTAL | Vismodegib intermittent schedule of 12 weeks vismodegib followed by 8 weeks placebo, repeated 3 times with a final course of vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up |
| Vismodegib Induction Followed by Intermittent Schedule | EXPERIMENTAL | Vismodegib beginning with 24 weeks induction followed by intermittent schedule 8 weeks placebo, 8 weeks vismodegib (total 72 weeks), followed by 52 weeks treatment-free follow up |
| Vismodegib - Locally Advanced | EXPERIMENTAL | Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity |
| Vismodegib - Metastatic | EXPERIMENTAL | Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity |
| Cohort 1: Vismodegib 150 mg | EXPERIMENTAL | Participants received vismodegib 150 mg orally daily for 12 weeks. |
| Cohort 2: Vismodegib 150 mg | EXPERIMENTAL | Participants received vismodegib 150 mg orally daily for 12 weeks. |
| Cohort 3: Vismodegib 150 mg | EXPERIMENTAL | Participants received vismodegib 150 mg orally daily for 8 weeks, followed by 4 weeks with no treatment, followed by a second 8-week vismodegib treatment period. |
| Vismodegib 150 mg | EXPERIMENTAL | Participants received 150 mg vismodegib orally once a day until disease progression, intolerable toxicity, or withdrawal from the study. If a participant had been receiving combination chemotherapy and/or biotherapy (FOLFOX, FOLFIRI, bevacizumab) in a parent study, the same combination chemotherapy and/or biotherapy as specified in the parent study could be continued in this study at the discretion of the investigator. |
| Placebo to vismodegib | PLACEBO_COMPARATOR | Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study. |
| Placebo + Ruxolitinib | ACTIVE_COMPARATOR | Participants will receive placebo (PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. |
| Vismodegib + Ruxolitinib | EXPERIMENTAL | Participants will receive vismodegib (150 mg PO QD) in combination with ruxolitinib (dose will depend on the participant's baseline platelet count) for up to 48 weeks. |
| 1 | EXPERIMENTAL | Control cohort with normal renal and normal hepatic function |
| 2 | EXPERIMENTAL | Severe renal impairment and normal hepatic function |
| 3 | EXPERIMENTAL | Mild hepatic impairment and normal renal function |
| 4 | EXPERIMENTAL | Moderate hepatic impairment and normal renal function |
| 5 | EXPERIMENTAL | Severe hepatic impairment and normal renal function |
| Vismodegib + rosiglitazone | EXPERIMENTAL | Participants received rosiglitazone 4 mg orally on Days 1 and 8 of the study. Participants also received vismodegib 150 mg orally once a day beginning on Day 2 until one of the following occurred; disease progression, intolerable toxicity, most probably attributable to vismodegib, or patient withdrawal of consent. |
| Vismodegib + oral contraceptive | EXPERIMENTAL | Participants received the oral contraceptive norethindrone 1 mg/ethinyl estradiol 35 µg (Ortho-Novum 1/35®) orally on Days 1 and 8 of the study. Participants also received vismodegib 150 mg orally once a day beginning on Day 2 until one of the following occurred; disease progression, intolerable toxicity, most probably attributable to vismodegib, or patient withdrawal of consent. |
| A | EXPERIMENTAL | - |
| B | EXPERIMENTAL | - |
| C | EXPERIMENTAL | - |
| Stage 1: GDC-0449 (150 mg) | EXPERIMENTAL | Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 milligram (mg) on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 150 mg, orally, continuing until disease progression (deterioration of evaluable lesions and/or tumor-related symptoms defined using Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST v1.0), maximum benefit, or intolerability. |
| Stage 1: GDC-0449 (270 mg) | EXPERIMENTAL | Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 270 mg, orally, continuing until disease progression, maximum benefit, or intolerability. |
| Stage 1: GDC-0449 (540 mg) | EXPERIMENTAL | Participants with any tumor received a single oral dose of GDC-0449 hard gelatin capsules at a dosage of 540 mg on Day 1. Beginning on Day 8, participants received once daily doses of GDC-0449 540 mg, orally, continuing until disease progression, maximum benefit, or intolerability. |
| Stage 2: BCC [GDC-0449 (150 mg)] | EXPERIMENTAL | Participants with basal cell carcinoma (BCC) received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. |
| Stage 2: BCC [GDC-0449 (270 mg)] | EXPERIMENTAL | Participants with BCC received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 270 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. |
| Stage 2:Safety Expansion Cohort [GDC-0449 (150 mg)] | EXPERIMENTAL | Participants received a daily oral dose of GDC-0449 hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. |
| Stage 2: New Formulation [GDC-0449 (150 mg )] | EXPERIMENTAL | Participants received a daily oral dose of GDC-0449 Phase II drug product hard gelatin capsules at a dosage of 150 mg starting on Day 1 and continuing until disease progression, maximum benefit, or intolerability. |
| Name | Type | Description |
|---|---|---|
| Vismodegib | DRUG | Vismodegib 150 mg hard gelatin capsule orally once daily |
| Placebo | DRUG | Vismodegib placebo orally once daily |
| FOLFOX | DRUG | FOLFOX (folinic acid \[FOL, leucovorin\], fluorouracil \[F, 5-FU\], and oxaliplatin \[OX\]) was supplied as solutions for intravenous administration. |
| FOLFIRI | DRUG | FOLFIRI (folinic acid \[FOL, leucovorin\], fluorouracil \[F, 5-FU\], and irinotecan \[IRI\]) was supplied as solutions for intravenous administration. |
| Bevacizumab | DRUG | Bevacizumab was supplied as a solution for intravenous administration. |
| Vismodegib 150 mg | DRUG | Vismodegib 150 mg was provided in hard gelatin capsules. |
| Placebo to vismodegib | DRUG | Placebo to vismodegib consisted of the excipients for vismodegib without the active molecule in hard gelatin capsules matching the active drug product in color and size. |
| Modified FOLFOX | DRUG | Following administration of bevacizumab, patients received oxaliplatin 85 mg/m\^2 IV administered over 90 minutes concurrently with folinic acid 400 mg/m\^2 (d,I-racemic form, or 200 mg/m\^2 I-isomer form) IV administered over 120 minutes, then fluorouracil 400 mg/m\^2 administered as an IV bolus, then 2400 mg/m\^2 administered as a continuous IV infusion over 46 hours. |
| Ruxolitinib | DRUG | Ruxolitinib will be administered PO BID at a starting dose depending on the participants's baseline platelet count for up to 48 weeks. |
| Rosiglitazone | DRUG | Rosiglitazone was supplied in tablets. |
| Norethindrone/ethinyl estradiol | DRUG | Norethindrone/ethinyl estradiol was supplied in tablets. |
| GDC-0449 | DRUG | Daily oral repeating dose |
Inclusion Criteria: * Adult participants, \>/= 18 years of age * Participants with multiple basal cell carcinomas, including participants with Gorlin syndrome, with at least 6 clinically evident basal cell carcinomas at the time of randomization, of which 3 measure 5 mm or more in diameter and are ...
GDC-0449 is an investigational small molecule being developed by Roche Holding AG for the treatment of solid cancers, including locally advanced or metastatic solid tumors that are refractory to standard therapy or for which no standard therapy exists. It is an oral Hedgehog pathway inhibitor and remains in clinical development.
GDC-0449 is being studied in adults with locally advanced or metastatic solid tumors, including tumors that are refractory to standard therapy or for which no standard therapy exists. It is an investigational agent and is not approved for any indication.
GDC-0449 targets the Hedgehog signaling pathway as a Hedgehog pathway inhibitor. By blocking this pathway, it is designed to interfere with signaling that contributes to tumor growth in solid cancers. It is a small molecule administered orally.
GDC-0449 is being developed by Roche Holding AG, which trades under the ticker RHHBY. Roche is the sponsor of the clinical program evaluating the drug in patients with advanced solid tumors.
GDC-0449 is in Phase 1 clinical development. It is an investigational drug and has not been approved by the FDA for any indication. The Phase 1 program has been completed, and no trials are currently active.
GDC-0449 has been evaluated in two completed Phase 1 trials: NCT00968981, which studied the Hedgehog pathway inhibitor in locally advanced or metastatic solid tumors refractory to standard therapy, and NCT00607724, which studied it in locally advanced or metastatic solid tumors. Both trials enrolled adults and are completed.
Yes. GDC-0449 is also referred to as GDC-0449 oral capsules (non-labeled). These names refer to the same investigational small molecule developed by Roche Holding AG for solid cancers.