Advanced Solid Tumors MedDRA version: 20.0 Level: LLT Classification code 10007050 Term: Cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: PM14
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Not applicable
Current Sponsor code: PM14
Other descriptive name: PM14
Concentration unit:
Sponsors
Pharma Mar, S.A.
Eligibility
Sex/Gender
All
Inclusion 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) Histologically or cytologically-confirmed selected advanced solid tumors (see below) for which the standard of care therapies have failed, or are intolerant to standard of care therapies that are known to provide clinical benefit. a) Gastrointestinal: esophageal carcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, biliary tract carcinoma, hepatocarcinoma and poorly differentiated (grade 3) gastroenteropancreatic neuroendocrine neoplasms (Ki 67 index >20%; mitotic count >20%). b) Lung: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). c) Sarcoma: liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing’s sarcoma. d) Gynecological: epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas and/or endometrial adenocarcinomas), endometrial carcinoma and carcinoma of cervix. e) Breast: ductal or lobular carcinoma. f) Genitourinary tract tumors: urothelial bladder carcinoma, clear cell renal carcinoma and prostate adenocarcinoma. g) Other: malignant pleural mesothelioma, extrapulmonary small cell carcinoma, and adrenocortical carcinoma. 5) In the Expansion stage only (tumor-specific cohort[s] at the RD): a) Measurable disease according to RECIST v.1.1. b) Documented disease progression per RECIST v.1.1 during or immediately after last therapy according to any of the aforementioned criteria. 6) Washout periods: a) At least three weeks since the last chemotherapy, radiotherapy (RT) >30 Gy, or monoclonal antibody (MAb)-containing therapy. b) At least two weeks since the last biological/investigational single-agent therapy (excluding MAbs) and/or palliative RT (=10 fractions or =30 Gy total dose). c) In patients with hormone-sensitive breast cancer progressing while on hormone therapy (except for luteinizing hormonereleasing hormone [LHRH] analogues in pre-menopausalwomen or megestrol acetate), all other hormonal therapies must be stopped at least one week before study treatment start. d) Castrate-resistant prostate cancer (CRPC) patients may continue receiving hormone therapy prior to and during study treatment. Note: washout periods will be referred to the day of first cycle administration (Day 1), not to the day of registration. 7) Adequate bone marrow, renal, hepatic, and metabolic function (assessed = 7 days before registration): a) Platelet count = 100 x 109/L, hemoglobin = 9.0 g/dL and absolute neutrophil count (ANC) = 2.0 x 109/L. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 x the upper limit of normal (ULN), even in the presence of liver metastases. c) Alkaline phosphatase (AP) = 2.5 x ULN (= 5 x ULN if diseaserelated/ in the case of liver metastases). d) Total bilirubin = 1.5 x ULN or direct bilirubin = ULN. e) Calculated creatinine clearance (CrCL) = 30 mL/minute (using Cockcroft-Gault formula). f) Creatine phosphokinase (CPK) = 2.5 x ULN. g) Serum albumin = 3.0 g/dL.* 8) 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. Are the trial subjects under 18? no Number of subjects for this ag
Exclusion criteria
Exclusion criteria: 1) Concomitant diseases/conditions: a) History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within the previous year. b) Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment. c) Myopathy or any clinical situation that causes significant and persistent elevation of CPK (> 2.5 x ULN in two different determinations performed one week apart). d) Ongoing chronic alcohol consumption or cirrhosis with Child- Pugh score B or C. Known Gilbert disease. e) Active uncontrolled infection. f) Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV) infection or active hepatitis B. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR. g) Any past or present chronic inflammatory colon and/or liverdisease, past intestinal obstruction, pseudo or sub-occlusion or paralysis. h) Evident symptomatic pulmonary fibrosis or interstitial pneumonitis, pleural or cardiac effusion rapidly increasing and/or necessitating prompt local treatment within seven days. i) Any other major illness that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study (e.g., COVID-19). 2) Prior treatment with lurbinectedin (Zepzelca®), trabectedin (Yondelis®) or topoisomerase I inhibitors is excluded, if the last dose was administered within six months prior to the first infusion of PM14 and irinotecan. 3) Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within two weeks prior to the first infusion of PM14 and irinotecan. 4) Active or untreated central nervous system (CNS) involvement. Exception: patients with previously treated CNS metastases are eligible provided they have to show radiographic stability (defined as no CNS progression for at least four weeks from postradiotherapy brain scan to brain scan performed during study screening), and patients should not have neurologic sign/symptoms secondary to the brain metastases or RT. Any steroid treatment must be completed =14 days before the first dose of study treatment. Note: for all SCLC patients regardless of prior history of brain metastases or patients with other solid tumors and previously treated CNS metastases, adequate CNS imaging (contrast enhanced-computed tomography [CT] or magnetic resonance imaging [MRI], if applicable) will be performed at baseline to document any disease involvement. 5) Limitation of the patient’s ability to comply with the treatment or follow-up protocol. 6) Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception. 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 six 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I dose escalation stage: To determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM14 in combination with irinotecan in patients with selected advanced solid tumors (Note: dose escalation with primary granulocyte colony-stimulating factor [G-CSF] prophylaxis may be implemented to determine the RD, in the event of dose-limiting toxicities [DLTs] of the combination being exclusively related to neutropenia). Phase II expansion stage: To confirm the RD determined during the dose escalation stage, and to evaluate the antitumor activity of PM14 and irinotecan in terms of overall response rate (ORR), according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 in patients with selected advanced solid tumors.;Secondary Objective: Evaluate the safety & tolerability of the combination in patients with selected advanced solid tumors Characterize the pharmacokinetics of this combination and detect potential major drug-drug PK interactions Evaluate pharmacogenetics in germline DNA by the presence or absence of PGt polymorphisms in genes relevant for PM14 disposition (distribution, metabolism and excretion) that may explain individual variability in main PM14 PK parameters Conduct an exploratory pharmacogenomics analysis substudy in tumor and blood samples from patients consenting to the substudy and exposed to PM14 and irinotecan, to identify potential biomarkers of response and/or resistance to the combination Dose escalation stage: obtain information on the antitumor activity of PM14 in combination with irinotecan Expansion stage: evaluate clinical benefit (ORR or stable disease [SD] lasting over 4 months) and timeto- event endpoints in terms of progression-free survival and duration of response (DoR).;Primary end point(s): Dose Escalation Phase: Determination of the Maximum Tolerated Dose and the Recommended Dose Definition of Dose-limiting Toxicities Expansion Phase: Overall Response Rate;Timepoint(s) of evaluatio | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Both stages: Safety Pharmacokinetics Pharmacogenetics Pharmacogenomics Efficacy;Timepoint(s) of evaluation of this end point: Along the study. | — |
Countries
Spain, United States
Contacts
Public ContactClinical Trials
Pharma Mar, S.A.
Outcome results
None listed