Carol M. Richman

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.

Systemic radiotherapy in metastatic breast cancer using 90Y-linked monoclonal MUC-1 antibodies

Radioimmunotherapy (RIT) is a promising approach for treating metastatic breast cancer. Initial clinical trials using 131I radioimmunoconjugates, and more recent studies employing 90Y, have demonstrated objective, although transient, antitumor effects in heavily pretreated patients with minimal toxicity. Antibodies targeting unique epitopes of epithelial glycoprotein mucin (MUC-1) on breast cancer cell surfaces that have been studied in patients include BrE-3 (murine and humanized) and m170 (murine). Both antibodies react with at least 90% of breast cancers. In these and other RIT trials, myelosuppression has been the dose-limiting toxicity. However, this toxicity has been successfully circumvented with the use of autologous peripheral blood stem cell transplantation, and recent clinical trials have escalated 90Y doses up to 50 mCi/m(2). The therapeutic index indicates that using these agents with stem cell support should deliver 9000 to 18000 rads to metastatic tumors. Development of improved chelates that are readily metabolized in the liver may reduce doses to this organ, projected to be next in line as dose-limiting. Combination therapy will be required to produce durable benefits in metastatic breast cancer. Low dose taxanes are synergistic with RIT in preclinical studies and when administered in the optimal sequence could sensitize tumor cells to the continuous low dose radiation delivered by RIT, without increasing toxicity. The addition of systemically administered tumor targeting radiation therapy using RIT as part of combined modality therapy may enhance the rate of complete response and, in patients with minimal metastatic disease, could lead to curative therapy.

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.

Impact of interpatient pharmacokinetic variability on design considerations for therapy with radiolabeled MAbs.

Radionuclides provide biologically-distributed vehicles for radiotherapy of multifocal cancer. Two algorithms, fixed vs individualized, have been used to prescribe the therapeutic dose of radionuclide (GBq) for the patient. The individualized method for prescribing radionuclide dose takes variations in drug pharmacokinetics into consideration, whereas the fixed method depends, in part, on documentation that there is little interpatient pharmacokinetic variability for the radiolabeled drug. Two data bases, selected to compare iodine-131((131)I) and indium-111((111)In) labeled MAbs, were used to assess interpatient pharmacokinetic variability and its impact on radionuclide dose prescription. Pharmacokinetic data obtained over 7 days for non-Hodgkins lymphoma (NHL) patients given (131)I-Lym-1 (n = 46) or (111)In-Lym-1 (n = 13) were used to obtain cumulated activities. Although (131)I-Lym-1 often showed greater interpatient variability, (111)In-Lym-1 showed several-fold variability for many tissues. Both (131)I- and (111)In-Lym-1 had sufficient interpatient variability to be significant for radionuclide dose prescription, depending on the dose-limiting critical tissue. Interpatient variability exceeded intra- and interoperator variability and intrapatient variability over time for a single institution. In summary, the magnitude of interpatient pharmacokinetic variability for (131)I- and (111)In-Lym-1 suggested that an optimally safe and effective therapy can be best achieved when radionuclide dose is influenced by estimated radiation dose, if the latter is reproducible from institution to institution.

Acute myocardial infarction in hemoglobin SC disease.

Although there are reports of myocardial infarction (MI) in patients with sickle cell diseases, an antemortem diagnosis of acute MI in a patient with compound heterozygous hemoglobin SC disease has not been reported. Herein, we present a patient with hemoglobin SC who suffered an acute MI. She had typical chest pain for myocardial ischemia, associated with ST elevations on the electrocardiogram (EKG) and elevations of cardiac injury markers diagnostic of infarction. The patient was treated with conventional therapies for acute coronary syndrome and also emergent red blood cell exchange. Interestingly, coronary angiography was completely normal in this patient. Potential mechanisms and management for acute MI in patients with sickle cell disease are discussed.

Does Paclitaxel (Taxol) Given after 111In-Labeled Monoclonal Antibodies Increase Tumor-Cumulated Activity in Epithelial Cancers?

Purpose: Paclitaxel synergized radiolabeled monoclonal antibodies, enhancing therapeutic effect in studies in mice with human xenografts. Paclitaxel was also observed to increase tumor uptake in imaging studies of 111In-DOTA-Gly3Phe-m170 in patients with breast and prostate cancers. Further evaluations of tissue-cumulated activities, therapeutic indices, and pharmacokinetics were done using data for patients with breast and prostate cancer and for mice with human breast cancer xenografts. Experimental Design: In radioimmunotherapy trials, 12 patients with breast or prostate cancer were given two imaging doses (5 mCi each) of 111In-DOTA-Gly3Phe-m170 1 week apart. Five of these patients were given a single dose of paclitaxel i.v. (75 mg/m2) 2 days after the second dose of 111In. In a subsequent study, athymic mice with human breast cancer xenografts were given 111In-DOTA-Gly3Phe-ChL6 alone, or in combination with daily paclitaxel i.p. (300 μg) one or more times. Pharmacokinetics were studied for at least 6 days in patients and 5 days in mice. Cumulated activities were determined for tumors and normal tissues. Results: Tumor-cumulated activity for every patient in the paclitaxel-treated group increased for the second dose of 111In-DOTA-Gly3Phe-m170. The median ratio of cumulated activities in tumors for imaging dose 2 to those for dose 1 was 1.0 (0.8-1.3) in patients that were not given paclitaxel and 1.3 (1.2-1.4) in patients given paclitaxel. Normal tissue-cumulated activities were not different for the two doses. Mice given paclitaxel 1 day after 111In-DOTA-Gly3Phe-ChL6 also showed an increase in tumor-cumulated activity, 22.9 (± 1.3) versus 19.4 (± 3.3) μCi h/g/μCi (P = 0.05). Cumulated activities of normal tissues were similar for all groups of mice. Conclusions: Paclitaxel given 1 to 2 days after 111In-DOTA-Gly3Phe-monoclonal antibody increased the tumor-cumulated activity in patients and in mice with epithelial cancers and did not alter cumulated activities in normal tissues.

Overview of Radioimmunotherapy in Advanced Breast Cancer Using I-131 Chimeric L6

131I chimeric L6 (ChL6) monoclonal antibody (MoAb) therapy has been performed in 12 patients with advanced, metastatic breast cancer. The protocol was designed to determine the maximum tolerated dose (MTD) of radioimmunotherapy that could be administered at 4 intervals. Ten patients received 20-70 mCi/m2 of 131I ChL6. Two of the patients received granulocyte colony stimulating factor (GCSF) on days 10-20 post therapy. The MTD for two doses was 60 mCi/m2 and thrombocytopenia was the dose limiting toxicity in the absence of marrow reconstitution with stem cells. Two patients received 150 mCi/m2 with autologous peripheral blood stem cell support 7 and 9 days post treatment. The MTD has not been reached for 131I-ChL6 with autologous stem cell support. In the 12 patients treated with 131I ChL6, six patients (50%) had measurable tumor regressions greater than 30% of the sum of the largest two dimensional products for measurable tumors. Four of these 6 patients had a partial response (PR), i.e., > or = 50% reduction in tumor size. These therapeutic responses associated with modest clinical toxicity in heavily pretreated patients suggest that clinically relevant radioimmunotherapeutic approaches can be devised for metastatic breast cancer.