A Study of Intravenous XMT-1001 in Patients With Advanced Solid Tumors

A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous XMT-1001 in Patients With Advanced Solid Tumors

This amended expansion phase of the protocol is to further the experience at a dose level of 150 mg CPT eq/m2 in patients with Stage IV non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and to test for preliminary anti-tumor activity in these tumor types. The MTD was initially defined as 113 mg CPT equivalents(eq)/m2 in the dose escalation part of the study. However, in the initial expansion phase (Protocol Amendment 11), 11 patients (10 NSCLC patients and 1 gastric cancer patients) were dosed at 113 mg CPT eq/m2 and less bone marrow toxicity was observed as compared to more heavily pre-treated patients in the dose escalation part of the study. Therefore, this amended expansion phase will investigate the safety and anti-tumor effects of a dose of 150 mg CPT eq/m2.

The study will also determine:

• The safety and tolerability of XMT-1001 at 150 mg CPT eq/m2
• The pharmacokinetics (PK) of XMT-1001 (how XMT-1001 behaves in the body) in patients Stage IV non-small cell lung carcinoma (NSCLC) and small cell lung cancer
• Evidence of XMT-1001 anti-tumor activity at 150 mg CPT eq/m2

This is an open-label study of XMT-1001 administered intravenously over 4 hours every 21 days (1 Cycle). Blood sampling for PK analyses will be performed immediately prior to dosing, and 9 times after dosing. Patients will be assessed for toxicities known to occur with other drugs of this class, such as bone marrow suppression, elevated liver function enzymes, hemorrhagic cystitis, and diarrhea. Tumor imaging will be performed every 2 cycles.

Inclusion Criteria:

1. At least 18 years old

2. Have histological or cytological documentation of one of the following:

   A. NSCLC with Stage IV disease according to the American Joint Cancer Commission TNM Staging (7th Edition)

   • Have received at least one prior chemotherapy regimen but no more than two chemotherapy regimens for their advanced disease (not containing irinotecan or topotecan).
   • Adjuvant chemotherapy will be considered as a prior chemotherapy regimen only if it is completed less than 6 months prior to enrollment.
   • Treatment with erlotinib or crizotinib as single agents will not be considered as a chemotherapy regimen for purposes of this trial OR B. SCLC with Stage IV (extensive) or recurrent disease after definitive treatment for limited stage disease according to the American Joint Cancer Commission TNM Staging (7th Edition)1
   • Have received at least one prior chemotherapy regimen but no more than two chemotherapy regimens for their advanced disease (not containing irinotecan or topotecan).
   • Adjuvant chemotherapy will be considered as a prior chemotherapy regimen only if it is completed less than 6 months prior to enrollment.

3. Patients must be refractory or resistant to standard therapy or for whom standard therapy is not anticipated to be curative and who have progressed through prior regimens.

4. Patients must have measurable disease with at least one lesion that can be accurately measured by Response Evaluation Criteria in Solid Tumors (RECIST). The lesion size must be ≥20 mm by conventional radiological techniques or ≥10 mm by spiral CT scan. Disease in an irradiated field as the only site of measurable disease is acceptable if there has been a clear progression of the lesion. PET scans are not suitable for providing these measurements. For patients who are sensitive to contrast, MRI may be used.

5. Patients with CNS metastases are acceptable provided that the disease has been treated (e.g. surgery, whole brain radiotherapy, stereotactic radiotherapy etc.) and the patient is stable for at least two weeks and does not require steroids (at least one week off steroids). Anti-seizure medication is allowed at the discretion of the treating physician.

6. At least 42 days since administration of mitomycin or nitrosoureas, and 28 days since any other chemotherapy, investigational agent, and/or radiation therapy.

7. Have the following laboratory values:

   • Absolute neutrophil count (ANC) ≥1500 cells/mm3

   • Platelet count >100,000 cells/mm3

   • Hemoglobin ≥9.0 g/dL

   • Adequate renal function (serum creatinine ≤2 mg/dL) and creatinine clearance ≥45 mL/min (Calculated by Cockroft and Gault method)

   • Adequate hepatic function (bilirubin ≤1.5 mg/dL)

   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 times the institutional upper limit of normal (ULN, or

     • 5 times the ULN if liver metastases are present)

   • Albumin of >3.0 g/dL

   • PT and PTT ≤1.5 times the ULN

8. Have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1.

9. Have a life expectancy of at least 3 months.

10. Have signed an informed consent form.