Robert T. O'Donnell

Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment

PURPOSE Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physicians decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). CONCLUSION Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.

High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.

Purpose: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. Experimental Design: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. Results: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. Conclusions:111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, “fractionated” therapy that could enhance clinical response.

Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non‐Hodgkin lymphoma

This phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non‐Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28‐d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty‐two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression‐free survival (PFS) was 12·4 months. The 13 rituximab refractory patients had an ORR of 61·5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow‐up time of 43 months, the median duration of response and time to next therapy were 15·4 and 37·4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low‐affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.

Disulfide cross-linked micelles for the targeted delivery of vincristine to B-cell lymphoma.

Vincristine (VCR) is a potent anticancer drug, but its clinical efficacy is limited by neurotoxicity. The field of drug delivery may provide an opportunity to increase the therapeutic index of VCR by delivering the drug specifically to tumor sites while sparing normal tissue. We have recently developed a telodendrimer (PEG(5k)-Cys(4)-L(8)-CA(8)) capable of forming disulfide cross-linked micelles (DCMs) which can encapsulate a variety of chemotherapeutics. In the present study, we encapsulated VCR into these micelles (DCM-VCR) and used them to treat lymphoma bearing mice. DCM-VCR particles have a size of 16 nm, which has been shown to be optimal for their accumulation into tumor via the enhanced permeability and retention (EPR) effect. Compared to our first-generation non-cross-linked micelles (NCMs), DCM-VCR demonstrated greater stability and slower drug release under physiological conditions. In addition, DCM-VCR exhibited a maximum tolerated dose (MTD) of 3.5 mg/kg while the MTD for conventional VCR was only 1.5 mg/kg. Using a near-infrared cyanine dye (DiD) as the surrogate drug, we showed that DCM-VCR accumulated at the tumor site starting 1 h after injection and persisted up to 72 h in lymphoma xenografted nude mice. In an in vivo efficacy study, high dose (2.5 mg/kg) DCM-VCR produced the greatest reduction in tumor volume. High dose DCM-VCR was well tolerated with no significant changes in complete blood count, serum chemistry and histology of the sciatic nerve. Mice treated with an equivalent dose (1 mg/kg) of conventional VCR and DCM-VCR controlled tumor growth equally; however, in combination with on-demand addition of the reducing agent N-acetylcysteine, DCM-VCR exhibited a superior antitumor effect compared to conventional VCR.

Importance of temporal relationships in combined modality radioimmunotherapy of breast carcinoma

The beneficial effects of radioimmunotherapy (RIT) may result from activation of molecular pathways that lead to programmed cell death (apoptosis). The influences of sequence and timing of 90Y‐DOTA‐peptide‐ChL6 antibody (90Y‐ChL6) and anti‐epidermal growth factor receptor antibody (ch225) or paclitaxel (Taxol; Bristol‐Myers Squibb, Princeton, NJ) on efficacy and toxicity were examined.

Early diagnosis and successful treatment of a patient with transfusion-associated GVHD with autologous peripheral blood progenitor cell transplantation.

BACKGROUND : Transfusion‐associated GVHD (TA‐GVHD) is an uncommon complication of blood transfusion. Diagnosis of TA‐GVHD is difficult, and it is usually rapidly fatal. There are few documented sur‐ vivors of TA‐GVHD.

Enhancement of the Therapeutic Index: From Nonmyeloablative and Myeloablative toward Pretargeted Radioimmunotherapy for Metastatic Prostate Cancer

Purpose: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. Experimental Design: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. 111In/90Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgen-independent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage (111In/90Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1 scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1 and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1 epitopes. Results: The nonmyeloablative maximum tolerated dose of 90Y-m170 was 0.74 GBq/m2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m2 of 90Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. Conclusions: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients. Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.

An evaluation of barriers to accrual in the era of legislation requiring insurance coverage of cancer clinical trial costs in California

PURPOSEClinical trials are essential to improve cancer therapy, but only 3% of newly diagnosed adult cancer patients enroll annually. We previously conducted a prospective analysis of factors affecting trial accrual at the UC Davis Cancer Center between 1997 and 2000. It was found that the accrual rate was 14% and that patients with private insurance were significantly less likely than patients with government insurance to enroll, suggesting that fear of insurance denial was a barrier. In 2002, a new California law (SB37) required insurers to reimburse routine costs of care for cancer trials. METHODSTo assess the impact of SB37 on accrual, we repeated our study using the same survey instrument. Oncologists seeing new patients at the UC Davis Cancer Center from August to November 2002 completed questionnaires that inquired about patient characteristics and eligibility, protocol availability, and patient willingness to participate. RESULTSPhysicians considered clinical trials for 55% (118/216) of patients, but trials were available for only 53% (62/118). Eligibility criteria were met by 82% (51/62). Of these, 69% (35/51) agreed to participate (vs 51% previously). No patient declined to participate because of insurance limitations (vs 8% previously). Furthermore, insurance type was no longer a significant factor in determining whether patients would enroll. This suggests that although the overall rate of accrual is only slightly increased after passage of SB37, patients may be more willing to enroll. Efforts to increase participation must include enhancing physician and patient awareness of SB37.

Phase I Trial of High-Dose Tamoxifen in Combination with Cisplatin in Patients with Lung Cancer and Other Advanced Malignancies

Background. Tamoxifen has been reported to enhance the antitumor activity of cisplatin in preclinical models by modulation of protein kinase C signal transduction and apoptosis-related pathways. Methods. We conducted a phase I study of high-dose oral tamoxifen in combination with intravenous cisplatin, with two objectives: 1) to determine tolerability, and 2) to determine the daily tamoxifen dose required to achieve serum levels equivalent to in vitro concentrations reported to enhance cisplatin cytotoxicity in preclinical models. Tamoxifen was administered days one through seven at escalating daily doses of160 mg/m2 (n=5),200 mg/m2 (n=6), and250 mg/m2 (n=4) by patient cohort, followed by cisplatin at 100 mg/m2 on day eight. Serum concentrations of tamoxifen and its hydroxylated metabolite N-desmethyltamoxifen were determined by high-performance liquid chromatography (HPLC) on day eight of the first treatment cycle in seven patients. Results. Fifteen patients with advanced malignancies received treatment with tamoxifen at 160 mg/m2, 200 mg/m2, and 250 mg/m2 per cycle, respectively. Serum concentrations of tamoxifen and N-desmethyltamoxifen on day eight of the first cycle ranged from 1.75–8.22 μM (mean 4.72 μM) and 3.62–10.85 μM (mean 3.87 μM), respectively. Toxicity analysis demonstrated that grade 3/4 nonhematological toxicity occurred in 0/5 at a tamoxifen dose of 160 mg/m2, 1/6 at a tamoxifen dose of 200 mg/m2, and in 1/4 patients at the 250 mg/m2 dose level. No grade 4 hematological toxicity occurred. Classic dose-limiting toxicity was not observed; the trial was closed to further accrual after documentation that targeted tamoxifen levels (around 5 μM) were achieved with daily tamoxifen doses≥160 mg/m2 in combination with cisplatin. Conclusions. This regimen of high-dose tamoxifen in combination with cisplatin can be safely administered. Serum tamoxifen levels comparable to concentrations required for enhancement of cisplatin sensitivity in vitro are clinically achievable with acceptable toxicity. The level of antitumor activity in nonsmall cell lung cancer NSCLC is encouraging (partial response in 4/10 patients). Based on these data, a Phase II study of high-dose tamoxifen in combination with cisplatin in patients with metastatic NSCLC is being conducted through the Southwest Oncology Group.

CD22 Antigen Is Broadly Expressed on Lung Cancer Cells and Is a Target for Antibody-Based Therapy

Most patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasis and extended overall survival. The finding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets.