Overview
The first part of the study (phase Ia - dose escalation) will evaluate the safety and tolerability and identify the dose-limiting toxicities (DLTs) of PM54.
The second part of the study (phase Ib - expansion) will be to evaluate the antitumor activity of PM54 in terms of clinical benefit (response or stable disease [SD] ≥4 months associated with tumor shrinkage), according to the RECIST v.1.1 and/or serum markers as appropriate, in patients with selected advanced solid tumors.
Eligibility
Inclusion Criteria:
- Voluntarily signed and dated written informed consent, obtained prior to any specific study procedure.
- Age ≥18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
- Phase Ia (dose escalation) stage: patients must have:
- Pathologically confirmed diagnosis of advanced solid tumors for whom no standard
therapy exists:
- Genitourinary tract tumors: urothelial carcinoma, clear cell renal carcinoma and prostate adenocarcinoma.
- Cutaneous melanoma.
- Gastrointestinal: esophageal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, and poorly differentiated (grade 3) gastroenteropancreatic Neuroendocrine Carcinoma (NEC )with Ki67 index >55%.
- Lung: non-small cell lung cancer (NSCLC) and Small Cell Lung Cancer (SCLC).
- Gynecological tumors: epithelial ovarian carcinoma (including primary peritoneal disease and/or fallopian tube carcinomas), endometrial adenocarcinoma and carcinoma of cervix.
- Breast: ductal or lobular.
- Sarcoma: liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing sarcoma.
- Deleterious germline BRCA1/2 mutation tumors.
- Other: malignant pleural mesothelioma, extrapulmonary small cell carcinoma, adrenocortical carcinoma.
- Pathologically confirmed diagnosis of advanced solid tumors for whom no standard
therapy exists:
Note: patients with measurable or non-measurable disease according to the
Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 are eligible during
this stage.
2. No more than three prior lines of chemotherapy.
5. Phase Ib (expansion) stage: patients must have:
1. Pathologically confirmed diagnosis of one of the following:
- High-grade Serous Ovarian Carcinoma (HGSOC) (including fallopian tube and
primary peritoneal carcinoma).
- Sarcomas (including liposarcoma, leiomyosarcoma [uterine or soft tissue],
synovial sarcoma and Ewing sarcoma).
- Small cell carcinomas (SCLC or extrapulmonary small cell carcinoma) or
poorly differentiated grade 3 gastroenteropancreatic NEC with Ki67 index
≥55%.
- Tumors with deleterious germline BRCA1/2 mutations.
- Cutaneous melanoma.
2. Measurable disease according to the RECIST v.1.1 and/or evaluable disease by
serum markers in case of prostate and ovarian cancer (according to the
Prostate-Specific Antigen Working Group Recommendations (PSAWGR) and the
Gynecologic Cancer Intergroup (GCIG) specific criteria, respectively).
3. Progressive disease after last therapy at study entry.
4. Patients must have received standard treatments:
- HGSOC: no more than three prior lines of chemotherapy. Patients should have
received previous therapy with poly(ADP-ribose) polymerase inhibitors
(PARPi) and anti-Vascular Endothelial Growth Factor (VEGF) (bevacizumab),
unless contraindicated. In case of germline BRCA1/2 mutation, the patient
will be included in the cohort of tumors with deleterious germline BRCA1/2
mutations (see below).
- Sarcomas: at least one but no more than two prior lines of chemotherapy.
- Small cell carcinomas/NEC: no more than two prior lines of chemotherapy.
- Tumors with deleterious germline BRCA1/2 mutations:
1. Breast cancer: no more than three prior lines of chemotherapy. Standard
therapies for hormone receptor (HR)-positive disease and/or anti-Her2
therapies (in the event of Her2-positive disease) should have been
completed. One line of immunotherapy is allowed in triple negative
disease.
2. Epithelial ovarian/fallopian tube/primary peritoneal carcinoma: no more
than three prior lines of chemotherapy.
3. Pancreatic adenocarcinoma: no more than two prior lines of
chemotherapy.
4. Prostate adenocarcinoma: no more than one prior line of chemotherapy.
Patients must have received one line of next-generation androgen
pathway inhibitors (i.e., enzalutamide, apalutamide, abiraterone or
darolutamide).
5. Tumors of other anatomical locations: no more than two prior lines of
chemotherapy. Prior use of PARPi is required for those indications
where use of PARPi has been approved by regulatory agencies.
- Cutaneous melanoma:
1. BRAF wild-type (WT) melanoma: at least one prior line of immunotherapy
for advanced disease. The patient may have received this therapy in the
adjuvant setting. No more than two prior lines of systemic therapy for
advanced disease. Note: patients with disease progression during
adjuvant therapy or within the first six months after the last dose of
adjuvant therapy will be considered as having been treated with one
prior line of treatment.
2. BRAF-mutated melanoma: at least one prior line of target therapy for
advanced disease with BRAF inhibitor with or without MEK-inhibitor, and
at least one prior line of immunotherapy for advanced disease. The
patient may have received any of these therapies in the adjuvant
setting. No more than three prior lines of systemic therapy for
advanced disease.
6. Recovery to grade ≤1 from drug-related AEs of previous treatments, excluding grade 2
alopecia, according to the NCI-CTCAE v.5.
7. Laboratory values within seven days prior to first infusion:
1. Absolute Neutrophil Count (ANC) ≥1.5 x 10^9/L, platelet count ≥100 x 10^9/L and
hemoglobin ≥9 g/dL (patients may be transfused for anemia as clinically indicated
prior to study entry).
2. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3.0 x ULN.
3. Total bilirubin ≤upper limit of normal (ULN) (up to 1.5 x ULN for patients with
Gilbert's syndrome).
4. Creatinine clearance ≥30 mL/min (calculated using the Cockcroft and Gault's
formula).
5. Serum albumin ≥3 g/dL. *
8. Washout periods:
1. At least three weeks since the last chemotherapy.
2. At least four weeks since the last monoclonal antibody (MAb)-containing therapy.
3. At least two weeks since the last biological/investigational single-agent therapy
(excluding MAbs) and/or palliative radiotherapy (RT).
4. 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.
5. 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.
- Albumin transfusion to increase the blood level in order to fulfill the
inclusion criterion is strictly forbidden.
Exclusion Criteria:
For both stages:
1. Concomitant diseases/conditions:
1. Increased cardiac risk:
- Uncontrolled arterial hypertension despite optimal management (≥160/100
mmHg).
- Presence of clinically relevant valvular disease.
- History of long QT syndrome.
- Corrected QT interval (QTcF, Fridericia correction) ≥450 ms on screening
ECG.
- History of ischemic heart disease, including myocardial infarction, unstable
angina, coronary arteriography or cardiac stress testing with findings
consistent with coronary occlusion or infarction ≤6 months prior to study
entry.
- History of heart failure or left ventricular dysfunction (left ventricular
ejection fraction [LVEF] ≤50%) by multiple-gated acquisition scan (MUGA) or
echocardiography (ECHO).
- Clinically relevant ECG abnormalities, including any of the following: right
bundle branch block with left anterior hemiblock, second (Mobitz II) or
third degree atrioventricular block.
- Symptomatic arrhythmia.
- Concomitant medication with risk of inducing torsades de pointes, which
cannot be discontinued or switched to an alternative drug prior to start
PM54 dosing.
- Use of a cardiac pacemaker.
2. Active infection requiring systemic treatment.
3. Known human immunodeficiency virus (HIV) or known hepatitis C virus (HCV)
infection or active hepatitis B.
4. 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. Symptomatic, steroid-requiring, and progressing central nervous system (CNS) disease.
Exceptions will be made for patients who have completed radiotherapy at least four
weeks prior to inclusion (asymptomatic patients taking steroids in the process of
already being tapered within two weeks prior to inclusion).
3. Patients with carcinomatous meningitis.
4. Prior bone marrow or stem cell transplantation.
5. Prior treatment with trabectedin, lurbinectedin, or PM14.
6. Use of (strong or moderate) inhibitors or strong inducers of CYP3A4 activity within
two weeks prior to the first infusion of PM54.
7. Known hypersensitivity to any of the components of the drug product.
8. Limitation of the patient's ability to comply with the treatment or to follow the
protocol procedures.
9. 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.