sirolimus and Genital-Neoplasms--Female

Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies.. Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined.. The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months.. Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Genital Neoplasms, Female; Humans; Quinazolines; Sirolimus; TOR Serine-Threonine Kinases

Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated.. We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates.. Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC.. Combination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. CLINICAL TRAILS INCLUDED: NCT01197170.

Topics: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Genital Neoplasms, Female; Humans; Kaplan-Meier Estimate; Middle Aged; Nitriles; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Triazoles; Young Adult

Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates.. Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted.. This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%).. DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Genital Neoplasms, Female; Humans; Middle Aged; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; ras Proteins; Sirolimus; Survival Rate

The mTOR inhibitor, temsirolimus, has clinical activity in the treatment of gynecologic malignancies, particularly endometrial cancer. We sought to determine the tolerability of the combination of weekly topotecan with weekly temsirolimus.. Women with a history of advanced or recurrent gynecologic malignancy refractory to curative therapy were enrolled. A starting dose of 1mg/m(2) of intravenous topotecan days 1, 8 and 15 was combined with 25mg temsirolimus days 1, 8, 15 and 22 of a 28 day cycle. Patients with and without prior pelvic radiotherapy (RT) were dose-escalated in separate cohorts.. Fifteen patients were treated on study. Forty-three cycles were administered, with between 1 and 7 cycles received per patient. Patient characteristics included ovarian cancer (n=7), endometrial cancer (n=3), uterine carcinosarcoma (n=3), and cervical cancer (n=2); performance status 0 (n=10) and 1 (n=5); prior chemotherapy regimens one (n=8), two (n=4), and three (n=3). Dose-limiting toxicity included asymptomatic neutropenia and thrombocytopenia. Four patients without prior pelvic RT were successfully treated with 1mg/m(2) topotecan with 25mg temsirolimus, days 1, 8, and 15 of a 28 day cycle. The combination was not tolerated in patients with a history of pelvic RT.. Dose-limiting toxicity for the combination of temsirolimus with topotecan was myelosuppression. The regimen may be safe in women who have not previously received radiation, but full doses of each agent could not be administered in combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genital Neoplasms, Female; Humans; Infusions, Intravenous; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Topotecan