Inhibitors of mTOR Clinical Trials

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Based on the preclinical data, a phase I trial evaluating the safety of CCI-779 was implemented (126). The results indicate that with daily intravenous treatment, there are significant grade 3 toxicities, including hypocalcemia, vomiting, thrombocytopenia, and increase in the level of hepatic transaminase. One patient had an objective response (non-small-cell carcinoma), and a number of patients had minor responses or stable disease (cervical carcinoma, uterine carcinoma, renal cell carcinoma, and soft tissue sarcoma). On a weekly treatment schedule, patients experienced no grade 3 toxicities regardless of dosage. Three patients had a partial tumor regression (renal cell, neuroendocrine, and breast carcinomas). Subsequently, based on the phase I results, phase II trials were initiated to study the effects treating advanced-stage refractory renal cell carcinoma with CCI-779 (127,128). The results of the two completed trials were positive, with an objective response rate of 5-7%, a minor response rate of 26-29%, and stable disease in approx 40% of the patients. Currently, phase III trials are in progress to test the efficacy of CCI-779 either alone or in combination with interferon-a as a first-line treatment of renal cell carcinoma. Results from the initial dose-finding and safety trials have prompted the development of a number of additional phase I and phase II trials for various forms of cancer. These include trials for breast cancer, prostate cancer, pancreatic cancer, malignant glioma, glioblastoma multiforme, endometrial cancer, renal cell carcinoma, and endometrial cancer. For a few of these studies, such as a prostate cancer study in which CCI-779 is used as a neoadjuvant to shrink tumors prior to prostatectomy, a comprehensive examination of the phosphorylation status and expression levels of the various components of the mTOR signaling pathway will be performed, including examination of the PTEN status in these tumors. This study will also monitor the S6K activity in peripheral blood mononuclear cells (PBMCs) because data from animal models indicate that this activity might serve as an indirect biomarker of the drug activity within the tumors (129). However, few of the other studies will collect comprehensive data about the mTOR pathway. This is unfortunate, because it is likely that such information would prove valuable in the future for targeting patient populations more likely to respond to CCI-779 treatment. This would, however, require a change in the design of clinical trials from a tumor-classification approach to a biomarker-based approach.

Drug

Table 1

Summary of Current Clinical Trials Using Rapamycin or Its Analogs

Title

Disease

Phase

CCI-779 Phase II Randomized Study of Neoadjuvant CCI-779 Followed by Radical Prostatectomy in Patients With Newly Diagnosed Prostate Cancer Who Have a High Risk of Relapse CCI-779 Phase II Randomized Study of Letrozole With or Without CCI-779 in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer CCI-779 Phase II Study of CCI-779 in Patients With Locally Advanced or Metastatic Pancreatic Cancer

CCI-779 Phase II Study of CCI-779

in Patients With Metastatic or Locally Advanced Recurrent Endometrial Cancer CCI-779 Phase II Study of CCI-779 in Patients With Recurrent Glioblastoma Multiforme CCI-779 Phase I/II Study of CCI-779 in Patients With Malignant Glioma

Adenocarcinoma of the prostate Stage II prostate cancer Stage I prostate cancer

Stage IIIB breast cancer Stage IIIC breast cancer Stage IV breast cancer Recurrent breast cancer

Stage II pancreatic cancer Stage III pancreatic cancer Stage IVA pancreatic cancer Stage IVB pancreatic cancer Recurrent pancreatic cancer Adenocarcinoma of the pancreas Endometrial cancer

Recurrent adult brain tumor Glioblastoma multiforme

Recurrent adult brain tumor Adult glioblastoma multiforme Adult anaplastic astrocytoma Adult anaplastic Oligodendroglioma Mixed gliomas

(not yet open)

I-II

As a result of the development of CCI-779, there are few clinical cancer trials testing rapamycin. However, there is currently an ongoing phase II trial examining the effect of rapamycin treatment on refractory renal cell carcinoma. There is also a phase I trial establishing safety in treatment of pediatric patients with refractory acute leukemias or lymphomas.

The initial results of the RAD001 phase I MTD trial using a fixed dosing schedule indicated mild toxicity with tumor responses observed in several patients (130).

Clinical data are lacking for the more recently developed inhibitors from Ariad. An initial phase I trial is currently underway for AP23573, and AP23841 is still in preclinical development. The current clinical trials that are open and recruiting for the various analogs of rapamycin are summarized in Table 1.

Table 1 (Continued)

Drug

Title

Disease

Phase

CCI-779

CCI-779

CCI-779

CCI-779

CCI-779

Rapamycin

Rapamycin

AP23573

A Phase 3, Three-Arm, Randomized, Open-Label Study of Interferon Alfa Alone, CCI-779 Alone, and the Combination of Interferon Alfa and CCI-779 in First-Line Poor-Prognosis Subjects With Advanced Renal Cell Carcinoma Phase III Randomized Study of Interferon Alfa Versus CCI-779 Versus Interferon Alfa and CCI-779 in Patients With Poor Prognosis Stage IV or Recurrent Renal Cell Carcinoma Phase II Study of CCI-779 in Patients With Previously Treated Mantle Cell Non-Hodgkin's Lymphoma Phase II Randomized Study of CCI-779 in Patients With Extensive-Stage Small Cell Lung Cancer Phase II Study of CCI-779 in Patients With Metastatic Melanoma Phase I/II Study of Sirolimus in Patients With Glioblastoma Multiforme Phase I Study of Sirolimus in Pediatric Patients With Relapsed or Refractory Acute Leukemia or Non-Hodgkin's Lymphoma

Carcinoma Renal cell Kidney Neoplasms

Recurrent renal cell cancer Stage IV renal cell cancer

A Phase I, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Daily o 5 Administration of AP23573, an mTOR Inhibitor, in Patients with Refractory or Advanced Malignancies

Recurrent mantle cell lymphoma

Extensive stage small-cell lung cancer

Stage IV melanoma Recurrent melanoma

Recurrent adult brain tumor Adult glioblastoma multiforme

Recurrent childhood Lymphoblastic lymphoma Recurrent childhood small noncleaved cell lymphoma Recurrent childhood large-cell lymphoma Recurrent childhood acute myeloid leukemia Recurrent childhood acute lymphoblastic leukemia Advanced, refractory or recurrent solid tumors Lymphoma Multiple myeloma

(suspended)

I-II

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