Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM.

METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance.

RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses.

Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.