Pharmacokinetic Study of PM01183 in Combination With Irinotecan in Patients With Selected Solid Tumors

• Status: Recruiting
• Trial end date: 2023-11-01
• Target enrollment: 0
• Participant gender: All

Summary

Prospective, open-label, dose-ranging, uncontrolled phase I study with PM01183 in combination with irinotecan to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with irinotecan in patients with selected advanced solid tumors.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: PharmaMar
• Treatments: Camptothecin; Irinotecan

Criteria

Inclusion Criteria:

1. Voluntarily signed and dated written informed consent prior to any specific-study procedure.

2. Age ≥ 18 years.

3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.

4. Life expectancy ≥ 3 months.

5. No more than two prior lines of cytotoxic-containing chemotherapy regimens for advanced disease. There is no limit for prior targeted therapy, hormonal therapy and immunotherapy (such as nivolumab).

6. Histologically or cytologically confirmed diagnosis of advanced disease of any of the following tumor types:

1. Glioblastoma.

2. Soft-tissue sarcoma [excluding gastrointestinal stromal tumors (GIST)].

3. Endometrial carcinoma.

4. Epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas) regardless of platinum sensitivity.

5. Mesothelioma.

6. Gastroenteropancreatic neuroendocrine tumors (GEP-NET).

7. Small cell lung cancer (SCLC).

8. Pancreatic adenocarcinoma.

9. Gastric carcinoma.

10. Colorectal carcinoma (CRC).

7. Expansion phase: Tumor-specific cohort(s) at the RD:

1. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.

For patients with glioblastoma: Measurable disease according to RECIST v.1.1 and RANO criteria.

2. Documented disease progression per RECIST v.1.1 during or immediately after last therapy according to any of the aforementioned criteria.

For patients with glioblastoma: Documented disease progression per RECIST v.1.1 and RANO criteria.

8. At least three weeks since the last anticancer therapy (excluding immunotherapy that must be at least two weeks, provided that is not combined with chemotherapy), including investigational drugs and radiotherapy, and at least six weeks since nitrosoureas and mitomycin C (systemic).

For patients with glioblastoma: at least 12 weeks since the end of radiotherapy, except if:

1. The patient has a new lesion outside of the radiotherapy field, or

2. The patient has undergone brain surgery to remove the tumor before study entry, and progressive disease has been confirmed histologically.

9. Adequate bone marrow, renal, hepatic, and metabolic function (assessed ≤ 7 days before inclusion in the study):

1. Platelet count ≥ 100 × 10^9/L, hemoglobin ≥ 9.0 g/dL and absolute neutrophil count (ANC) ≥ 2.0 × 10^9/L.

2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × the upper limit of normal (ULN), even in the presence of liver metastases.

3. Alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN if disease-related/in the case of liver metastases).

4. Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN.

5. International Normalized Ratio (INR) < 1.5 (except if patient is on oral anticoagulation therapy).

6. Calculated creatinine clearance (CrCL) ≥ 30 mL/minute (using Cockcroft-Gault formula).

7. Creatine phosphokinase (CPK) ≤ 2.5 × ULN.

8. Albumin ≥ 3.0 g/dL(*).

10. Recovery to grade ≤ 1 or to baseline from any adverse event (AE) derived from previous treatment (excluding alopecia and/or cutaneous toxicity and/or peripheral neuropathy and/or fatigue grade ≤ 2).

(*)Albumin transfusion to increase the blood level in order to fulfill the inclusion criterion is strictly forbidden.

Exclusion Criteria:

1. Concomitant diseases/conditions:

1. History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year.

2. Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment.

3. Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 × ULN in two different determinations performed one week apart).

4. Ongoing chronic alcohol consumption or cirrhosis with Child-Pugh score B or C. Known Gilbert disease.

5. Active uncontrolled infection.

6. Known human immunodeficiency virus (HIV) infection. Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B.

7. Any past or present chronic inflammatory colon and/or liver disease, past intestinal obstruction, pseudo or sub-occlusion or paralysis.

8. Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days.

9. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.

2. Prior treatment with PM01183, trabectedin (Yondelis®) or topoisomerase I inhibitors (irinotecan, topotecan, etc.). Prior topoisomerase inhibitors (e.g., irinotecan) are only allowed in patients with colorectal carcinoma.

3. Prior bone marrow or stem cell transplantation, or radiation therapy in more than 35% of bone marrow.

4. Known brain metastases or leptomeningeal disease involvement. Glioblastoma lesions (primary or locally advanced) are eligible. In SCLC, patients with brain metastases or leptomeningeal disease involvement are eligible provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment (patients taking steroids in the process of already being tapered within two weeks prior to screening are allowed). Brain CT-scan or MRI results must be provided at baseline.

5. Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception.(*)

6. Limitation of the patient's ability to comply with the treatment or follow-up protocol.

(*)Women of childbearing potential (WOCBP) must agree to use an effective contraception method to avoid pregnancy during the course of the trial (and for at least three months after the last infusion). Fertile male patients must agree to refrain from fathering a child or donating sperm during the trial and for four months after the last infusion.