Clinical Trials

Date: 2017-05-01

Type of information: Publication of results in a medical journal

phase: 1-2

Announcement: publication of results in Cancer

Company: Immunogen (USA - MA)

Product: IMGN853 - mirvetuximab soravtansine

Action mechanism: antibody drug conjugate (ADC). Mirvetuximab soravtansine (IMGN853) is a FRalpha-targeting antibody drug conjugate (ADC) developed and wholly owned by ImmunoGen. It is the first and only ADC to this target to enter clinical testing, and comprises a FRalpha-binding antibody conjugated to DM4, a potent cancer-cell killing agent developed by ImmunoGen specifically for use in ADCs. The antibody serves to target the DM4 specifically to FRalpha-positive cancer cells which the DM4 can then kill. FRalpha is highly expressed on many cases of epithelial ovarian cancer, and on other types of solid tumors including endometrial cancer and some non-small cell lung cancers. Mirvetuximab soravtansine is currently being assessed for the treatment of FRalpha-positive, platinum-resistant ovarian cancer and for FRalpha-positive relapsed/refractory endometrial cancer, with additional assessments anticipated.

Disease: FRalpha-positive platinum-resistant ovarian cancer

Therapeutic area: Cancer - Oncology

Country:

Trial details: The open-label, Phase 1 dose-escalation study treated a total of 44 patients with recurrent ovarian (52%) or endometrial cancer (25%), along with renal cell carcinoma and non-small cell lung cancer (11% and 9%, respectively). Patients received mirvetuximab soravtansine on day 1 of a 21-day cycle (Q3W dosing) with cycles repeated until dose-limited toxicity or progression, concluding the recommended dose for future trials is 6.0 mg/kg of mirvetuximab (based on adjusted ideal body weight) dosed once every three weeks.

Latest news:

• • On May 1, 2017, ImmunoGen announced that the results from a Phase 1 dose-escalation study evaluating mirvetuximab soravtansine (IMGN853) in patients with folate receptor alpha (FRalpha)-positive solid tumors were published in the journal Cancer. The previously disclosed data demonstrated encouraging clinical activity and a manageable safety profile for mirvetuximab soravtansine (IMGN853), and informed the dose that was used in Phase 1 expansion cohorts and the ongoing Phase 3 FORWARD I trial of patients with platinum-resistant ovarian cancer.
• Mirvetuximab soravtansine exhibited a manageable safety profile and encouraging preliminary clinical activity. Adverse events (AEs) were generally mild with the majority being grade 1 or grade 2 (least severe grades). The most commonly observed AEs were fatigue, blurred vision and diarrhea. The publication is entitled "Phase I dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor alpha-targeting antibody-drug conjugate, in patients with solid tumors". • On March 12, 2017, ImmunoGen announced that data from a mirvetuximab soravtansine (IMGN853) Phase 1 biopsy expansion cohort demonstrate that archival tumor tissue can reliably identify patients with folate receptor alpha (FRalpha)-positive platinum-resistant ovarian cancer. These data will be presented at the Society of Gynecologic Oncology (SGO) Annual Meeting, which is being held March 12-15 in National Harbor , MD. The objectives of the biopsy expansion cohort were to:
• - Characterize FRalpha expression in archival tumor tissue and in pre- and post-treatment biopsy samples obtained from a heterogeneous population of relapsed epithelial ovarian cancer (EOC) patients;
• - Determine the concordance rate between archival tissue and pre-treatment biopsy FRalpha expression levels; and
• - Compare changes in FRalpha expression levels before and after treatment with mirvetuximab soravtansine in biopsy samples.
• In the biopsy expansion cohort, a total of 27 heavily pretreated patients (including patients with up to 11 prior therapies) were enrolled based on FRalpha expression levels in archival tumor tissue. Patients underwent a pre-treatment biopsy prior to receiving mirvetuximab soravtansine and a post-treatment biopsy after two doses of mirvetuximab soravtansine.
• A comparison of FRalpha levels in pre-treatment biopsies versus archival samples supports the use of archival tumor tissue for patient selection. Of the 21 evaluable pre-treatment samples, 15 met the eligibility criterion for the biopsy expansion cohort (? 25% cells with ? 2+ intensity), resulting in a 71% concordance with archival tumor tissues. Twenty-two percent (22%) of patients (6/27) did not have pre-treatment biopsies evaluable for FRalpha immunohistochemistry due to insufficient tumor cells present in the specimens. Additionally, biopsies taken prior to and following two doses of mirvetuximab soravtansine showed similar FRalpha expression levels. The findings also support the use of a pre-treatment biopsy for patient selection if archival tumor tissue is not available for evaluation.
• The safety profile of the cohort was consistent with that previously reported for mirvetuximab soravtansine-treated EOC patients across the Phase 1 study, with predominately Grade 1 and 2 adverse events. Based on FR? expression in both archival and pre-treatment biopsies, the data also demonstrated that anti-tumor activity increased with higher FR? expression levels.
• • On December 28, 2016, ImmunoGen announced that results from the Phase 1 expansion cohort evaluating mirvetuximab soravtansine (IMGN853) in patients with folate receptor alpha (FRalpha)-positive platinum-resistant ovarian cancer were published in the Journal of Clinical Oncology . The data demonstrate the potential clinical benefit of mirvetuximab soravtansine for the treatment of platinum-resistant ovarian cancer. The Phase 1 expansion cohort enrolled 46 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer whose tumors were positive for FRalpha. Patients were dosed with mirvetuximab soravtansine once every three weeks. Mirvetuximab soravtansine demonstrated single-agent activity in the 46-patient cohort with a 26% confirmed response rate and median progression free survival (PFS) of 4.8 months. In a subset of 23 patients with low, medium or high FR?, who had received three or fewer prior lines of therapy, there was a 39% objective response rate (ORR) and median PFS of 6.7 months. On the basis of the study findings and additional data demonstrating the importance of FRalpha expression levels with mirvetuximab soravtansine, the Company has designed the Phase 3 FORWARD I study to enroll patients with platinum-resistant ovarian cancer with one to three prior therapies and with medium or high FRalpha. This group of patients in the Phase 1 expansion cohort exhibited a 44% ORR and a median PFS of 6.7 months. Mirvetuximab soravtansine exhibited a manageable safety profile. Adverse events (AEs) were generally mild with the majority being grade 1 or grade 2 (least severe grades). The most commonly observed AEs were diarrhea, blurred vision, nausea, and fatigue.
• • On May 18, 2016, ImmunoGen reported the clinical data from a 46-patient Phase 1 cohort evaluating the efficacy and safety of mirvetuximab soravtansine as single-agent therapy for platinum-resistant, folate receptor alpha (FRalpha)-positive ovarian cancer. These results have informed the Company's selection of the patient population and primary endpoint for a Phase 3 study scheduled to begin before year-end. This Phase 1 cohort, which was expanded from 20 to 46 patients to provide additional information for the design of subsequent trials, enrolled patients with platinum-resistant ovarian cancer who had received up to five previous treatment regimens. Patients also needed to have FRalpha expressed at or above a predefined level on at least 25% of tumor cells. Patients were classified as having low, medium, or high FRalpha expression based on the percent of tumor cells meeting this criterion (25-49%, 50-74%, and 75-100%, respectively). Among the 46 patients, 23 had high, 14 had medium, and 9 had low expression of FRalpha. All had previously received platinum and a taxane.
• Among all 46 patients, the confirmed objective response rate (ORR) was 26% and median progression-free survival (PFS) was 4.8 months (95% confidence interval, 3.9-5.7 months). Among the 16 patients who received up to three prior regimens and had high or medium FRalpha expression - the population selected for the planned Phase 3 trial - the ORR was 44% and median PFS was 6.7 months (95% CI, 3.9-11.0 months). For the 30 patients with low FR? and/or who had received four or five prior regimens, ORR was 17% and median PFS was 4.2 months (95% CI, 2.6-5.5 months).
• Current single-agent therapies for platinum-resistant ovarian cancer typically have an ORR of 15-20% and median PFS of 3-4 months, including in patients receiving no more than two prior regimens.
• Based upon the findings in this Phase 1 cohort, the planned Phase 3 trial assessing mirvetuximab soravtansine as single-agent therapy for platinum-resistant ovarian cancer will enroll patients who previously received up to three treatment regimens and whose cancer has high or medium FRalpha expression, with PFS as the primary endpoint.
• Mirvetuximab soravtansine was generally well tolerated, with most side effects Grade 1 or 2 (least severe grades). Of particular note, incidence of blurred vision was reduced from 55%, mostly Grade 2, in the first 20 patients enrolled to 39%, mostly Grade 1, among the 26 patients added with the expansion of the cohort. Other side effects reported in more than 20% of patients were diarrhea, fatigue, nausea, vomiting, peripheral neuropathy, increased AST, keratopathy, and abdominal pain.
• • On November 8, 2015, ImmunoGen reported findings with mirvetuximab soravtansine, its novel folate receptor alpha (FRalpha)-targeting ADC product candidate, being presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (abstract #C47). Analysis of the association between the amount of FRalpha present on patient cancer cells and response to treatment with mirvetuximab soravtansine found nine of ten (90%) patients with high levels of FR? had an objective response on treatment. The findings presented are from an analysis of 20 efficacy-evaluable patients with platinum-resistant ovarian cancer who received mirvetuximab soravtansine in Phase 1 testing at its selected dose. Patients were categorized as having high, medium or low amounts of FRalpha on their cancer cells.1Enrollment criteria for the clinical study required all patients to have at least low expression.
• Nine of the ten patients with high FRalpha expression had an objective response (2 complete responses/CRs, 7 partial responses/PRs by RECIST 1.1 criteria). Six of these responders remained on treatment for at least 24 weeks. The six patients with medium expression all had tumor regression. One patient had an objective response (unconfirmed PR) and one had tumor shrinkage with new lesion formation (mixed response/MR). An additional patient remained on treatment for more than six months but did not have an objective response. Four patients had low expression and none had an objective response. One patient was still on treatment at the time of data cut off for presentation. The ORR was 50% for all 20 efficacy-evaluable patients. Among all 22 patients evaluable for tolerability, the majority of adverse events reported were low grade (grade 1 or 2), with diarrhea, blurred vision, vomiting, fatigue, and nausea the most common treatment-emergent events reported ( > 30% of patients). ImmunoGen anticipates reporting mature data from the full 46-patient cohort in this study at a medical meeting in 2016.
• • On May 30, 2015, ImmunoGen announced the presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting of the first clinical findings in a disease-specific patient population with the Company's FRalpha-targeting ADC, mirvetuximab soravtansine. The findings reported are from an ongoing Phase 1 trial. Once the recommended Phase 2 dose (RP2D) of mirvetuximab soravtansine was established during dose finding (abstract #5558), an expansion cohort was opened to assess the safety and activity of this ADC specifically in the treatment of patients with FRalpha-positive platinum-resistant ovarian cancer. Approximately 80% of the patients screened have met the criteria for having FRalpha-positive disease.
• Twenty-two patients were included in the analysis reported - two from the dose-escalation phase of the trial and the twenty enrolled in the expansion cohort at the time of data cutoff for presentation (4/30/15). All had FRalpha-positive platinum-resistant ovarian cancer and had received mirvetuximab soravtansine at the RP2D (6.0 mg/kg, given every three weeks). All had previously received taxane as well as platinum therapy. Thirteen were still on study at the time of data cutoff. The majority of adverse events reported were low grade (grade 1 or 2), with diarrhea, blurred vision, nausea, vomiting, fatigue, and abdominal pain the most common treatment-emergent events reported ( > 20% of patients). Seventeen of the 22 patients were included in the efficacy analysis; the other five patients were still on study and had not yet reached their first assessment.
• Nine of these 17 patients had an objective response (8 partial responses, 1 complete response) to treatment, for an ORR of 53%. The responses in six of these nine patients were ongoing at the time of data cutoff, with five of these six patients on treatment for more than 15 weeks. Immunogen is now implementing a development plan to initiate a Phase 2 trial in late 2015 that will assess this ADC as a single-agent treatment for patients with FRalpha-positive platinum-resistant ovarian cancer.
• The findings reported are from a Phase 1 trial assessing mirvetuximab soravtansine for the treatment of FRalpha-positive solid tumors. After the RP2D was established in patients likely to have FRalpha-positive disease using a once every 3-week dosing schedule, an expansion cohort was opened to evaluate the ADC specifically in patients with FRalpha-positive platinum-resistant ovarian cancer when administered as a single agent at this RP2D. To be eligible for enrollment in this expansion cohort, patients must have ovarian cancer that responded to primary platinum therapy, but then progressed within six months or progressed on or within six months of treatment with subsequent platinum therapy. The cancer also must be FRalpha-positive, assessed by immunohistochemistry. Approximately 80% of patients screened met this criteria based on the CLIA lab assay. This expansion cohort has been expanded from 20 to 40 patients to obtain additional experience in this patient population.

Is general: Yes