Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM14 in Combination with Irinotecan in Pretreated Patients with Selected Advanced Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharma Mar S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Jul 2021 → 16 Jul 2025

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514890-24-00

EudraCT number

2021-000415-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Pharmacodynamic

• 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 objectives 6

1. To evaluate the safety and tolerability of this combination in patients with selected advanced solid tumors.
2. To characterize the pharmacokinetics (PK) of this combination and to detect potential major drug-drug PK interactions
3. To evaluate pharmacogenetics (PGt) 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.
4. To conduct an exploratory pharmacogenomics (PGx) 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 of PM14 and irinotecan.
5. Dose escalation stage: To obtain information on the antitumor activity of PM14 in combination with irinotecan
6. Expansion stage: To evaluate clinical benefit (ORR or stable disease [SD] lasting over four months [SD ≥4 months]) and time-to-event endpoints in terms of progression-free survival (PFS) and duration of response (DoR), if appropriate

Conditions and MedDRA coding

Patients with Selected Advanced Solid Tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 hormone-releasing hormone [LHRH] analogues in pre-menopausal women 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 disease-related/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).

Exclusion criteria 6

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 liver disease, 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 post-radiotherapy 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. Valid methods to determine childbearing potential, adequate contraception and requirements of WOCBP partners are described in APPENDIX 2

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Dose escalation stage: Determination of MTD and RD: the MTD will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients develop a DLT in Cycle 1. This protocol follows European terminology; thus, the RD and the MTD are not equivalent. Expansion cohorts will be performed starting at this resultant RD, not at the MTD
2. Expansion stage: Overall response rate, defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR), from the start of treatment to the date of progression or the start of a subsequent therapy or end of patient’s follow-up, according to the RECIST v.1.1, as appropriate.

Secondary endpoints 5

1. Safety: patients will be evaluable for safety if they have received at least one partial infusion of irinotecan and/or PM14. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. Additionally, treatment-related discontinuations and treatment compliance (dose reduction, skipped doses and/or treatment delays due to AEs), will be described
2. Pharmacokinetics: PK analyses will be evaluated in plasma by standard non-compartmental analysis (population pharmacokinetic modeling may be performed if appropriate). Plasma samples for PK analysis will be obtained in Cycle 1 from all patients.
3. Pharmacogenetics: the presence or absence of PGt polymorphisms in genes relevant for PM14 disposition (distribution, metabolism and excretion) from a single blood sample collected at any time during the trial (but preferably at the same time as the pre-treatment PK sample on Day 1 of Cycle 1) will be assessed to explain individual variability in main PM14 PK parameters
4. Pharmacogenomics: the mutational status and the expression levels of potential predictive factors of response and/or resistance to PM14 and irinotecan treatment will be analyzed from available tumor and/or blood samples obtained at diagnosis and/or during treatment (at response and/or relapse). Their correlation with the clinical response and outcome after treatment will be assessed.
5. Efficacy: patients will be evaluable for efficacy if they receive at least one complete infusion of both PM14 and irinotecan and have at least one clinical or radiological tumor assessment as per RECIST v.1.1, or if they are considered to have failed treatment. Treatment failure will be defined as symptomatic/clinical deterioration (disease related) or clinical progression, death due to malignant disease or treatment discontinuation due to any treatment-related AE before any appropriate tumor

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharma Mar S.A.

Sponsor organisation

Pharma Mar S.A.

Address

Avenida De Los Reyes 1, Poligono Industrial La Mina Poligono Industrial La Mina

City

Colmenar Viejo

Postcode

28770

Country

Spain

Scientific contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Public contact point

Organisation

Pharma Mar S.A.

Contact name

Clinical Development Oncology Unit

Third parties 4

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications