Study Design and Treatment

During the screening study, CD30 expression was assessed in eligible patients with GCTs, SCSTs, unclassified sex cord tumors, and unclassified testicular tumors. Seven patients with CD30‐expressing disease were subsequently enrolled in the treatment study from May 2012 to February 2014 and were treated with brentuximab vedotin administered via intravenous infusion over a period of 30 minutes on day 1 of each 21‐day cycle. Patients enrolled under the original protocol received an initial dose of 1.8 mg/kg Q3W (Cohort 1), the recommended single‐agent dose for the treatment of relapsed or refractory HL and systemic ALCL. However, the original phase I dose escalation study of brentuximab vedotin in hematological malignancies (NCT00430846) demonstrated acceptable toxicity up to a dose level of 2.7 mg/kg Q3W. Therefore, after completion of enrollment of Cohort 1 in this study, the protocol was amended to evaluate a second cohort of patients dosed with 2.4 mg/kg brentuximab vedotin Q3W. Following enactment of the amendment, patients who were initially treated with 1.8 mg/kg brentuximab vedotin Q3W (Cohort 1) and were still on‐study could also have their dose increased to 2.4 mg/kg Q3W at the discretion of the investigator. Dose reductions for tolerability were allowed during the course of the study. Response assessments were performed at cycles 2 and 4 and every four cycles thereafter while the patient was receiving treatment. Efficacy assessments included radiographic tumor imaging of the chest, abdomen, and pelvis graded using Response Evaluation Criteria in Solid Tumors version 1.1 [27]. Patients with stable disease or better were eligible to continue treatment with brentuximab vedotin until disease progression, unacceptable toxicity, or study closure. In addition, physical examination, serum chemistry panels, coagulation panels, complete blood counts with differential, performance status, and select vital sign measurements were performed on day 1 of each cycle. Patients were monitored for unacceptable toxicities. Adverse events were recorded for the safety reporting period from day 1 predose through the end of treatment visit or 30 days after the last study treatment, whichever was later.

Case 1

A 24‐year‐old male patient initially presented with a poor‐risk, metastatic, mixed testicular GCT (60% embryonal cell and 40% choriocarcinoma). He had lung, liver, and brain metastases; retroperitoneal disease; and a human chorionic gonadotropin (HCG) level >180,000 mIU/mL. The patient underwent a left radical orchiectomy, a left suboccipital craniotomy, and gamma knife radiation treatment to the cerebellum. Frontline chemotherapy included three cycles of bleomycin, etoposide, and cisplatin (BEP) and one cycle of etoposide and cisplatin (EP). He subsequently relapsed with pulmonary disease and was treated with one cycle of paclitaxel and gemcitabine, followed by a HDCT regimen consisting of two cycles of carboplatin plus etoposide with autologous stem cell rescue and radiation therapy to the right hilum. After relapsing again, he received additional salvage therapy with four cycles of gemcitabine, oxaliplatin, and paclitaxel. After achieving a best response of stable disease, his disease progressed 5 months later. At that point his archived orchiectomy tumor specimen was evaluated for CD30 expression, which was found to be present in 90% of tumor cells, and he was enrolled in the treatment study.

At baseline staging, the patient's HCG was 5,571 mIU/mL, and he had target lesions on the spleen, periaortic lymph node, right lobe of the lung, and right iliacus muscle (Table ​(Table1).1). The patient began treatment with brentuximab vedotin 1.8 mg/kg Q3W. His HCG decreased to 1,924 mIU/mL after the first cycle of treatment and further decreased to 45 mIU/mL after the second treatment cycle. Cycle 2 response assessments indicated a partial response to therapy. After two additional cycles of brentuximab vedotin, he experienced an increase in HCG to 502 mIU/mL and a further increase to 4,076 mIU/mL after the fourth cycle. At that point a computed tomography (CT) scan also showed evidence of disease progression at multiple sites. No additional therapy was given, and the patient subsequently died of progressive disease approximately 8 months after coming off the study.

Table 1.

Clinical features of patients with germ cell tumors or sex cord stromal tumors treated with brentuximab vedotin

Open in a separate window

H‐score (range 0–300) was calculated as the product of the intensity of CD30 staining (0–3) multiplied by the percentage of positively staining cells (0–100).

^aThis patient achieved a partial response at a single time point only.

^bMetastatic disease displayed pure EC histology.

Abbreviations: AFP, alpha‐fetoprotein; BL, baseline value; C, cycle; D, day; EC, embryonal carcinoma; GCT, germ cell tumor; H‐score, histo score; HCG, human chorionic gonadotropin; min, minimum on‐study value; N, normal or not performed.

Case 2

A 33‐year‐old male patient presented with a poor‐risk, metastatic, mixed testicular GCT consisting of EC, choriocarcinoma, and teratoma. He initially presented with an enlarged left supraclavicular lymph node, large bilateral pulmonary metastases, retroperitoneal disease, and a tumor in his right testis. The patient's HCG was 133,161 mIU/mL. Frontline treatment included four cycles of etoposide, ifosfamide, and cisplatin (VIP). Prior to the start of therapy, a biopsy of his left supraclavicular lymph node revealed 75% EC, 20% choriocarcinoma, and 5% mature teratoma. After completing four cycles of VIP, he underwent a delayed orchiectomy that revealed only mature teratoma. He then relapsed with his HCG increased, and he was found to have a new brain metastasis that was treated with stereotactic radiosurgery, with complete disappearance of his tumor. He was then treated with an HDCT regimen of carboplatin and etoposide, followed by an autologous stem cell transplant. Stable disease was achieved for 1 month, after which the patient's disease progressed. At that point, his left supraclavicular lymph node sample was evaluated for CD30 expression and was found to have 90% of malignant cells stain positive for CD30 by IHC. He was then enrolled in the treatment study.

At the baseline visit, the patient's HCG was 10,401 mIU/mL. Lesions were present in a left supraclavicular lymph node, right and left upper lungs, and a left retroperitoneal lymph node (Table ​(Table1).1). The patient began receiving brentuximab vedotin at a dose of 1.8 mg/kg Q3W. His HCG decreased to 832 mIU/mL following the first treatment cycle, decreased further to 111 mIU/mL following the second cycle, and reached a nadir of 53 mIU/mL after the third treatment cycle. Tumor assessments following cycle 2 indicated stable disease with no progression of target lesions and no new nontarget lesions. Following the fourth treatment cycle, the patient's HCG increased to 439 mIU/mL, but radiologically he continued to have stable disease. After cycle 5 of brentuximab vedotin, the patient's HCG had increased to 1,186 mIU/mL, and his left lung lesion had increased in size. New lesions were also present in the liver and lung. The patient was considered to have progressive disease and discontinued treatment with brentuximab vedotin. The patient subsequently died of progressive disease less than 2 months after coming off the study.

Case 3

A 58‐year‐old male patient was diagnosed with a metastatic pure EC with good risk per the IGCCCG criteria. He underwent a left radical orchiectomy followed by four cycles of BEP at an outside institution and achieved stable disease. He relapsed with metastatic disease in the retroperitoneal lymph nodes and was treated with a HDCT regimen of two cycles of carboplatin and etoposide and tandem autologous stem cell transplant. He achieved stable disease but relapsed after 7 months with liver and mesenteric metastases, at which time he received oral etoposide. A duodenal mass sample was evaluated for CD30 expression and was determined to be 100% CD30‐positive. He then enrolled in the treatment study.

At baseline, the patient had two lesions on the liver, a mesenteric mass on the small intestine (Table ​(Table1),1), and HCG and alpha‐fetoprotein (AFP) within the normal range. The patient received one cycle of brentuximab vedotin at a dose of 1.8 mg/kg but experienced multiple adverse events and subsequently discontinued treatment. At the end of treatment visit, the patient's imaging studies showed unequivocal progression of nontarget lesions in the liver. The patient subsequently had rapid deterioration and died of progressive disease 2 months after coming off the study.

Case 4

A 26‐year‐old male patient initially presented with a right testis mass and underwent a right radical orchiectomy. Tumor pathology demonstrated a mixed GCT composed of 90% EC and smaller components of seminoma and teratoma. On staging, he was found to have metastatic disease involving the lungs and retroperitoneal, mediastinal, and left supraclavicular lymph nodes. Tumor markers were normal. For good risk, stage III‐A, mixed NSGCT, he received four cycles of EP and achieved a partial response with normalization of his tumor markers but had residual retroperitoneal nodes and small remaining lung nodules. Although a retroperitoneal lymph node dissection demonstrated no evidence of viable disease, shortly thereafter he was found to have enlarging mediastinal lymph nodes and lung nodules without elevated tumor markers. Viable EC was demonstrated on a thoracoscopic biopsy specimen. The patient was treated with HDCT using a regimen of paclitaxel and ifosfamide followed by carboplatin and etoposide, including three cycles of high‐dose carboplatin and etoposide, each followed by stem cell reinfusion. He achieved a near complete response and was again placed on surveillance. However, approximately 5 months later, he was noted to have enlarging right lower lobe lung nodules and underwent a right lower lobectomy and regional lymph node dissection, with pathology demonstrating viable EC in both right lower lobe lung nodules as well as intralobular lymph nodes. On active surveillance, the patient developed progression in the lungs and mediastinal lymph nodes approximately 2 months later. He was enrolled in a phase II clinical trial of 5‐fluorouracil, oxaliplatin, and leucovorin plus alvocidib (flavopiridol, Tolero Pharmaceuticals, Inc.) but progressed after two cycles. A lung tumor sample from the patient's thoracotomy was evaluated for CD30 expression by IHC and was found to be 100% CD30‐positive. He was subsequently enrolled in the treatment study.

At baseline, the patient had lesions on the medial, lower right lobe of the lung and on the inferior hilum of the right lung (Table ​(Table1).1). Nontarget lesions were also present in supraclavicular and mediastinal lymph nodes. The patient began receiving brentuximab vedotin at a dose of 1.8 mg/kg Q3W. He achieved a partial response after two cycles, with the right lung lesion completely resolving and the right hilar lesion decreasing in size, and converted to a complete response after four cycles (Fig. ​(Fig.2).2). The patient continued treatment with brentuximab vedotin 1.8 mg/kg Q3W, and a complete response to treatment was maintained through the cycle 12 response assessment (Fig. ​(Fig.2).2). After 14 cycles of therapy, he began experiencing progressive lower extremity weakness, with difficulty climbing stairs and pain in his posterior calves. On examination, he was noted to have lower extremity weakness, including decreased strength in bilateral ankle plantar and dorsiflexion and hyporeflexia of the knees and ankles. Strength in the wrist extensors bilaterally was more subtly decreased. Peripheral sensory and motor neuropathy events, including those observed in this patient, are known side effects of treatment with brentuximab vedotin [28]. Given these symptoms and findings, cycle 15 was not administered and the patient was subsequently placed on close monitoring. As of his last follow‐up, complete response has been maintained without evidence of disease at more than 46 months from his last dose of brentuximab vedotin and over 55 months from study enrollment. He has had near complete resolution of weakness in his hands with significant improvement in strength in his lower extremities.

Open in a separate window

Figure 2.

Treatment with brentuximab vedotin induced a complete response in a patient (Case 4) with a germ cell tumor. Computed tomography scans over time of a right lung nodule (A), second right lung nodule (B), and mediastinal lymph node (C) in the patient in Case 4 who was treated with 1.8 mg/kg brentuximab vedotin. After cycle 2, the patient achieved a partial response that converted into a durable complete response after cycle 4.

Case 5

A 28‐year‐old male patient was diagnosed with an anterior mediastinal GCT composed of 95% EC and 5% seminoma/yolk sac tumor. He received frontline therapy of four cycles of BEP and achieved a partial response, after which his disease relapsed in the anterior mediastinum and subcarinal lymph nodes. He then received one cycle of paclitaxel, cisplatin, and ifosfamide. The patient's mediastinal tumor was assessed for CD30 expression and was found to be 80% CD30‐positive by IHC. The patient subsequently enrolled in the treatment study.

At baseline, he had disease in his mediastinum, carina, and aortic arch (Table ​(Table1),1), and his AFP was elevated at 152 ng/mL. The patient received one cycle of 2.4 mg/kg brentuximab vedotin but began experiencing symptomatic deterioration 1 week after the first dose and subsequently discontinued treatment. The patient died of progressive disease approximately 5 months after discontinuing the study drug.

Case 6

A 32‐year‐old male patient presented with a diagnosis of stage I seminoma. The patient underwent a radical right orchiectomy with adjuvant radiation to the right iliac and periaortic lymph nodes, after which he remained disease‐free for approximately 2.5 years. He then relapsed radiographically in an interaortocaval lymph node and was treated with three cycles of BEP, followed by retroperitoneal and right iliac lymph node dissections, spermatic cord excision, and retroperitoneal mass excision. Pathology revealed residual GCT with a question of EC and seminoma elements. Subsequently, he had no evidence of disease for approximately 19 months, at which point a chest x‐ray demonstrated new bilateral pulmonary metastases. The patient received one cycle of VIP and sought further medical attention for consideration of a tandem transplant. At that time, the previous pathology specimens were re‐examined and the patient's tumor was determined to be a Sertoli cell tumor and not a seminoma as originally diagnosed. He underwent two cycles of paclitaxel and gemcitabine and a thoracotomy with wedge resection of pulmonary metastases, but his disease progressed. The patient was subsequently enrolled in a clinical trial of the gamma secretase (Notch) inhibitor MK‐0752, which he discontinued because of an adverse event. The patient's thoracotomy sample was evaluated for CD30 expression and was found to be 98% CD30‐positive by IHC. He was then enrolled in the treatment study.

At baseline, the patient had target lesions on the subcarinal lymph node, the paratracheal lymph node, the lower lobes of the right and left lungs, and the left supraclavicular lymph node (Table ​(Table1).1). The patient initiated treatment with 1.8 mg/kg brentuximab vedotin Q3W and received four cycles of treatment. He achieved stable disease after two cycles of treatment, but all lesions showed evidence of progression at the cycle 4 assessment visit. Treatment with brentuximab vedotin was then discontinued, and the patient died 9 months later from progressive disease.

We thank Chantelle Rein‐Smith of Whitsell Innovations, Inc., for aid in manuscript preparation (funded by Seattle Genetics, Inc.). T.B. is currently affiliated with Willamette Valley Cancer Institute, Eugene, OR.