Phase i clinical trials in solid tumors

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Currently, a large number of phase I trials for bortezomib either as a single agent or in combination with conventional chemotherapy are underway (see Table 1). In this section, we expound on the details of some of these trials. Most results are available only in abstract form at the present.

Recently, results of a phase I trial by Aghajanian et al. have been published. In this study, 43 patients in a variety of neoplasms were treated with single-agent bortezomib in doses ranging from 0.13 to 1.56 mg/m2/dose. The tumor types included were non-small-cell lung cancer (NSCLC), colon, head and neck, melanoma, ovary, renal, prostate, bladder, cervix, endometrial, esophagus, gastric, and unknown primary. A total of 89 doses were administered, with an average of 2 cycles per patient. The median number of previous chemotherapeutic regimens was four. Reported DLTs were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. One partial response was seen in a patient with NSCLC. The maximum tolerated dose (MTD) was established at 1.56 mg/m2. Pharmacodynamics studies showed a dose-related inhibition of 20S proteasome activity with increasing dose of bortezomib (56).

Other phase I trials for single-agent bortezomib have preliminary results that have been presented in abstract form (62,63). In one study, bortezomib was given twice a week for 4 out 6 wk cycles in 22 patients with advanced cancer in doses ranging from 0.5 to 1.7 mg/ m2. Common reported toxicities were fatigue, anorexia, diarrhea, nausea, vomiting, fever,

Table l

Bortezomib Phase I Solid Tumor Trials

Table l

Bortezomib Phase I Solid Tumor Trials

Solid Tumor

Treatment

(mg/m2)

DLTs

Site/Status

Advanced

Bortezomib,

Pending

Mayo Clinic

solid tumors

paclitaxel,

carboplatin

Breast (57)

Bortezomib,

Pending

Neutropenic fever,

docetaxel

neurotoxicity,

lover, GI, mucositis

Advanced solid

Bortezomib

1.56

GI, neurotoxicity

tumors (56)

Ovarian (58)

Bortezomib,

Pending

Memorial Sloan-

carboplatin

Kettering Cancer

Center (open)

Glioma

Bortezomib

Johns Hopkins (open)

Advanced solid

Bortezomib,

1.00

Hematologic, GI,

tumors (59)

gemzar

1000

cardiac, liver

Advanced

Bortezomib,

Pending

Johns Hopkins

solid tumors

docetaxel

Lung (NSCLC)

Bortezomib,

Pending

City of Hope Cancer

gemcitabine,

Center (open)

carboplatin

Advanced

Bortezomib,

Pending

University of

solid tumors

carboplatin,

Colorado (open)

etoposide

Advanced

Bortezomib,

Pending

NYU (open)

malignancies

oxaliplatin

Advanced solid

Bortezomib,

0.7

GI

University of Southern

tumors (60)

fluorouracil,

500

California (closed)

leucovorin

20

Advanced solid

Bortezomib

Pending

NYU

tumors or

lymphomas

Advanced

Bortezomib

Pending

University of

malignancies

Wisconsin (open)

and renal

insufficiency

Metastatic or

Bortezomib,

Pending

Yale (open)

unresectable

topotecan

malignancy

Advanced solid

Bortezomib,

1.3

Hematologic, GI,

tumors (61)

irinotecan

125

partial small bowel

obstruction

Locally advanced Bortezomib,

Pending

Ohio State (open)

or metastatic

paclitaxel

solid tumors

Advanced

Bortezomib,

University of

solid tumors

doxorubicin

Pending

Wisconsin

Head and neck

Bortezomib,

Pending

NIH (open)

radiotherapy

Source: www.cancer.gov unless otherwise specified.

Source: www.cancer.gov unless otherwise specified.

and thrombocytopenia. Dose-dependent decreases in 20S proteasome activity in peripheral blood mononuclear cells (PBMNCs) were observed as well as increases in levels of p53. The MTD was not reported at the time; and in 18 evaluable patients, no objective responses were observed.

Bortezomib was administered in escalating doses ranging from 0.5 to 1.3 mg/m2 twice weekly, followed by 500 mg/m2 5-FU and 20 mg/m2 LV for 4 wk with 2 wk of rest, in a combination study with 5-FU/LV. Twenty-one patients were enrolled (15 colorectal, 1 esophageal, 1 breast, 1 anal, and 2 unknown). With 19 patients evaluable for response, 8 patients had stable disease, 10 had disease progression, and 1 (esophageal) had a partial response to the treatment. The MTD was determined to be 0.7 mg/m2 and the major DLT was gastrointestinal toxicity (60) (updated via personal communication with Dr. Iqbal and Dr. Lenz).

In another combination study, bortezomib and docetaxel were administered in patients with anthracycline-pretreated metastatic breast cancer. Bortezomib was given on d 1, 4, 8, and 11, and docetaxel was given 1 h before bortezomib on d 1. Dose levels evaluated were (mg/m2 bortezomib/mg/m2 docetaxel):1.0/60, 1.0/75, 1.3/75, and 1.0/100. The MTD was not reached at the time of abstract publication, and the DLTs reported were febrile neutropenia, neuropathy, transaminitis, mucositis, vomiting, and diarrhea (64).

Fifty-one patients with advanced solid tumors were enrolled in a phase I bortezomib/ irinotecan dose escalation study. Bortezomib dosing levels were 1.0, 1.3, and 1.5 mg/m2, and the dose of irinotecan ranged from 50 to 125 mg/m2. Secondary end-points included tumor response, 20S proteosome inhibition, and pharmacokinetics. Major DLTs reported were neutropenia, partial small bowel obstruction, diarrhea, rash, vomiting, and thrombocytopenia. Most frequent complaints were fatigue, diarrhea, and nausea. The combination therapy did not appear to result in additive toxicities, and pharmacokinetic interactions were not seen. The MTD was established at the1.3/125 (bortezomib/irinotecan) level, and two patients (gastroesophageal [GE] junction adenocarcinoma and ovarian cancer) had a response to the treatment (61).

The toxicity and efficacy of bortezomib/gemcitabine combination therapy was recently evaluated. Thirty-one patients with various advanced malignancies were enrolled. The MTD was determined to be 1.0/1000 (bortezomib/gemcitabine) mg/m2. DLTs reported included thrombocytopenia, leucopenia, neutropenia, nausea, vomiting, myocardial infarction, and hyperaminotransferasemia. Out of five patients with refractory NSCLC, one achieved a partial response under the combination regimen. The pharmacokinetics of bor-tezomib and its effect on proteasome inhibition in peripheral blood cells was similar to that when used as a single agent. Furthermore, combination therapy did not affect significantly the pharmacokinetics of each individual agent (62).

Recently, preliminary results of a dose-escalation trial of bortezomib with concurrent radiation therapy in patients with recurrent or metastatic head and neck were presented. Bortezomib was given twice weekly starting at 0.6 mg/m2/dose with radiation at 1.8 Gy and daily fractions to 60-72 Gy. At the time of abstract presentation, seven patients had been treated at two dose levels (0.6 and 0.9 mg/m2), with four patients showing marked reduction in tumor size. However, three of these patients subsequently progressed after 3 mo. No DLTs were observed at 0.6 mg/m2. At 0.9 mg/m2, G3 orthostatic hypotension and hyponatremia were seen (65).

To summarize, numerous phase I trials have shown the relative tolerability of bortezomib either as a single agent or in combination with chemotherapy or radiation. Major toxicities were hematological, gastrointestinal, and neuropathic. It is especially encouraging to see that combination therapy did not seem to cause a marked increase in toxicity.

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