Phase Ib/II, multicohort, single arm, open-label, multicenter, international clinical trial, with 6 cohorts (advanced STS, advanced L-sarcomas, other advanced sarcomas, advanced solid tumors, and localized STS) with 4 sites in Spain for phase I.
The aim of this study is to explore different infusions of PM14 (longer or repeated) in order to obtain a potentially better efficacy and similar toxicity profile in advanced soft tissue sarcoma patients as monotherapy and also in other solid tumors as concomitant treatment with radiation therapy.
Treatment
Cohort A
A phase I dose-finding stage for PM14 is planned with an estimated number of 20-25 patients. PM14 will be tested at different dose levels in 24-h IV infusion on day 1 of 21-day cycles, up to progression or unacceptable toxicity. Premedication with dexamethasone is recommended on the day before treatment initiation.
Cohort B
A phase I dose-finding stage for PM14 is planned with an estimated number of 20-25 patients. PM14 will be tested at different dose levels in 3-h IV infusion during 3 consecutive days (days 1-3) of 21-day cycles, up to progression or unacceptable toxicity. Premedication with dexamethasone is recommended on the day before treatment initiation.
Cohort E
PM14 will be administered at the recommended phase II dose (RP2D) according to the most convenient scheme. Cycles will be administered by central venous port. Premedication with dexamethasone is recommended on the day before treatment initiation. Cycles will be repeated every 21 days up to progression or unacceptable toxicity.
Cohort F
PM14 will be administered at the RP2D according to the most convenient scheme. Cycles will be administered by central venous port. Premedication with dexamethasone is recommended on the day before treatment initiation. Cycles will be repeated every 21 days up to progression or unacceptable toxicity.
Cohort C
Phase I: PM14 will be administered at the RP2D according to the most convenient scheme in 21-day cycles, at at different dose levels in combination with radiotherapy, up to progression or unacceptable toxicity. Cycles will be administered by central venous port. Premedication with dexamethasone is recommended on the day before treatment initiation and during 2 additional days (in the 24-hour infusion) and during 3 additional days (in the 3-hour infusion). Radiation therapy will start within 1 hour of PM14 infuser disconnection and will be administered with 3 Gy per fraction for 10 days (30 Gy in total).
Phase II: PM14 will be administered at RP2D concomitant with radiation therapy.
Cohort D
Phase I: PM14 will be administered at the RP2D according to the most convenient scheme, in up to 3 x 21-day cycles in neoadjuvant setting, at different dose levels in combination with radiotherapy. Cycles will be administered by central venous port. Premedication with dexamethasone is recommended on the day before treatment initiation. Radiation therapy will start within 1 hour of PM14 infuser disconnection and will be administered with 1.8 Gy per fraction for 25 days (45 Gy in total).
Phase II: PM14 will be administered at RP2D concomitant with radiation therapy.
The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
Age: 18-75 years.
Patients must have a diagnosis of soft tissue sarcoma with metastasis, and not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis confirmation will be performed and the tumor sample must be available and sent prior to inclusion to this end.
A centralized diagnosis of DD liposarcoma or mixoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E.
Performance status ≥ 2 (ECOG).
Plasma bilirubin > ULN.
Creatinine > 1.6 mg/dL.
History of other cancer with less than 5 years free of disease with the exception of adequately treated basal cell carcinoma or in situ cervical cancer.
Single group
PM14
DrugPharmaceutical form: PM14 drug product is provided as a sterile lyophilized powder for concentrate for solution for infusion with a strength of 5.0 mg of the active moiety. Route of administration: PM14 drug product was developed for administration by the i.v. route. Before use, the vials are reconstituted with 10 mL of sodium chloride 9 mg/mL (0.9%) solution for infusion to give a solution containing 0.5 mg/mL of PM14. Prior to administration, the reconstituted DP solution should be further diluted with sodium chloride 9 mg/mL (0.9%) solution for infusion. Each vial of PM14 5.0 mg is a single use vial.
Cohorts A, B, C To determine the maximum tolerated dose (MTD) of PM14 to be used as recommended phase 2 dose (RP2D).
The MTD will be determined by assessing adverse events according to CTCAE v5.0 and they will be used as a rule for escalating or diminishing dose levels according to the dose-limiting toxicities detailed in the protocol.
Cohorts E and F To evaluate the progression-free survival rate (PFSR) at 6 months.
PFSR-6m (according to central radiology review): Efficacy measured by the PFSR at 6 months, which is defined as the percentage of patients whodid not experience radiological progression according to RECIST v1.1 or death due to any cause since the date of enrollment until month 6 after date of enrollment
Cohort C phase I To determine the maximum tolerated dose (MTD) of PM14 to be used as recommended phase 2 dose (RP2D).
The MTD will be determined by assessing adverse events according to CTCAE v5.0 and they will be used as a rule for escalating or diminishing dose levels according to the dose-limiting toxicities detailed in the pro
Cohort C phase II To evaluate the overall response rate (ORR) in irradiated nodules only.
This objective is considered as a surrogate of palliative relief. Overall response rate (ORR) (according to central radiology review): Efficacy measured by ORR, which is defined as the number of patients with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable patients (according to RECIST v1.1). Only nodules included in the radiation field will be considered.
Cohorts A, B, E, F, C, D To evaluate the safety profile
Toxicity will be assessed by adverse events related to study drugs, detected through physical examinations and laboratory tests, and graded according to CTCAE v5.0.
Cohorts A, B, E, F, C, D To evaluate the overall response rate (ORR).
Overall response rate (ORR) (according to central radiology review): Efficacy measured by ORR, which is defined as the number of patients with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of responseevaluable patients (according to RECIST v1.1).
Cohorts A, B, C, D To evaluate the median of progression-free survival (mPFS).
mPFS (according to central radiology review): Efficacy measured by mPFS, which is defined as the median of time in months from date of enrollment to date of radiological progression according to RECIST v1.1 or to date of death due to any cause, whatever occurs first.
Cohorts A, B, E, F, C To evaluate quality of life.
Quality of life: Assessed by using the European Organization for Cancer Research and Treatment quality of life questionnaire (EORTC QLQ-C30). For the completion of the QLQ-C30 questionnaire, values between 1 and 4 (1: not at all, 2: a little, 3: quite a bit, 4: very much) are assigned according to the patient's responses to the item, only in items 29 and 30 are They evaluate with a score of 1 to 7 (1: very poor, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. High values on the global health and function status scales indicate a better quality of life (QoL), while on the symptom scale it would indicate a decrease in QoL since it indicates the presence of symptoms associated with cancer.
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