Trial of different schemes of PM14 alone and in combination with radiotherapy in soft tissue sarcomas and other solid tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Asoc Grupo Espanol De Investigacion En Sarcomas

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05], Diseases [C] - Neoplasms [C04]

Trial duration

23 Nov 2021 → ongoing

Decision date (initial)

2024-12-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-519893-38-00

EudraCT number

2021-001186-20

ClinicalTrials.gov

NCT05146440

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Therapy, Efficacy, Pharmacodynamic

COHORTS A (24-h IV PM14 in advanced sarcomas) and B (3-h IV PM14 3 consecutive days in advanced sarcomas)
Phase I: To determine the maximum tolerated dose (MTD) of PM14 to be used as recommended phase 2 dose (RP2D).
COHORTS E (24-h IV PM14 or 3-h IV PM14 3 consecutive days - Expanded to advanced L-sarcomas) and F (24-h IV PM14 or 3-h IV PM14 3 consecutive days - Expanded to other advanced STS: non L-sarcomas)
Phase II: To evaluate the progression-free survival rate (PFSR) at 6 months.
COHORT C (Best scheme of PM14 plus RTP (3 Gy x 10 days = 30 Gy) in advanced solid tumors: sarcoma, head and neck, and others)
Phase I: To determine the MTD of PM14 to be used as RP2D.
Phase II: To evaluate the ORR in irradiated nodules only. This objective is considered as a surrogate of palliative relief.
COHORT D (Best scheme of PM14 + RTP (1.8 Gy x 25 days = 45 Gy) in
localized intermediate sarcoma)
Phase I: To determine the MTD of PM14 to be used as RP2D.
Phase II: To evaluate the ORR.

Secondary objectives 36

1. Phase I: To evaluate the safety profile. (COHORTS A AND B)
2. Phase I: To evaluate the overall response rate (ORR). (COHORTS A AND B)
3. Phase I: To evaluate the median of progression-free survival (mPFS).(COHORTS A AND B)
4. Phase I: To evaluate quality of life. (COHORTS A AND B)
5. Phase I: To contribute to translational studies. (COHORTS A AND B)
6. Phase I: To characterize the PK of PM14 in the explored regimens. (COHORTS A AND B)
7. Phase II: To evaluate the overall response rate (ORR). (COHORTS E AND F)
8. Phase II: - To evaluate the median of overall survival (mOS). (COHORTS E AND F)
9. Phase II: To evaluate quality of life. (COHORTS E AND F)
10. Phase II: - To evaluate the safety profile. (COHORTS E AND F)
11. Phase II: To contribute to translational studies. (COHORTS E AND F)
12. Phase I: To evaluate the safety profile. (COHORT C)
13. Phase I: To evaluate the overall response rate (ORR). (COHORT C)
14. Phase I: To evaluate the median of progression-free survival (mPFS).(COHORT C)
15. Phase I. To evaluate quality of life. (COHORT C)
16. Phase I: To contribute to translational studies. (COHORT I)
17. Phase II: To evaluate variations in pain. (COHORT C)
18. Phase II: To evaluate variations in analgesic use. (COHORT C)
19. Phase II. To evaluate variations in quality of life. (COHORT C)
20. Phase II: To evaluate the overall response rate (ORR). (COHORT C)
21. Phase II: To evaluate the time to progression (TTP) of the irradiated nodules. (COHORT C)
22. Phase II: To evaluate the progression-free survival rate (PFSR) at 6 months. (COHORT C)
23. Phase II. To evaluate the median of overall survival (mOS). (COHORT C)
24. Phase II. To evaluate the pathological response. (COHORT C)
25. Phase II: To evaluate the safety profile. (COHORT C)
26. Phase II. To contribute to translational studies. (COHORT C)
27. Phase I. To evaluate the safety profile. (COHORT D)
28. Phase I. To evaluate the overall response rate (ORR). (COHORT D)
29. Phase I. To evaluate the median of progression-free survival (mPFS). (COHORT D)
30. Phase I. To evaluate the pathological response. (COHORT D)
31. Phase I. To contribute to translational studies. (COHORT D)
32. Phase II. To evaluate the pathological response. (COHORT D)
33. Phase II. To evaluate relapse-free survival (RFS) at 3 years. (COHORT D)
34. Phase II. To evaluate changes in MRI diffusion/perfusion parameters (exploratory). (COHORT D)
35. Phase II. To evaluate the safety profile. (COHORT D)
36. Phase II. To contribute to translational studies. (COHORT D)

Conditions and MedDRA coding

Soft tissue sarcomas and other solid tumors

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 35

1. Patients must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care. (All cohorts)
2. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA. (All cohorts.)
3. HBV and HCV serologies must be performed prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study). (All cohorts)
4. Patient must have a central venous catheter for PM14 treatment. (All cohorts)
5. 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. (Cohorts A, B, E, and F: PM14 monotherapy in advanced disease)
6. A centralized diagnosis of sarcoma, which includes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sclerosing epithelioid fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, sarcoma NOS, fibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, epithelioid sarcoma, clear cell sarcoma, dedifferentiated or aggressive features in solitary fibrous tumor, extraskeletal myxoid chondrosarcoma, angiosarcoma, epithelioid hemangioendothelioma, well-differentiated/dedifferentiated liposarcoma and myxoid liposarcoma. A centralized diagnosis of DD liposarcoma or myxoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E. (Cohorts A, B, E and F)
7. Patients must have received a previous chemotherapy line in advanced disease, unless contraindicated or not indicated. (Cohorts A, B, E and F).
8. Radiological disease progression must be documented within 6 months prior to study entry. (Cohorts A, B, E and F).
9. Patients must have been considered eligible for systemic chemotherapy. A maximum of three previous lines in cohorts A and B and two previous lines in cohorts E and F for advanced/metastatic disease are allowed. (Cohorts A, B, E and F).
10. Patients must have a diagnosis of advanced soft tissue sarcoma, or recurrent head & neck suitable for reirradiation or other advanced or metastatic solid tumor not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis will be performed, and the tumor sample must be available and sent prior to PM14 start. For phase II part, only soft tissue sarcomas will be enrolled. (Cohort C).
11. Patients must have received a previous chemotherapy line in advanced disease. (Cohort C)
12. A centralized diagnosis of sarcoma, which includes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sclerosing epithelioid fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, sarcoma NOS, fibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, epithelioid sarcoma, clear cell sarcoma, dedifferentiated or aggressive features in solitary fibrous tumor, extraskeletal myxoid chondrosarcoma, angiosarcoma, epithelioid hemangioendothelioma, … A centralized diagnosis of DD liposarcoma or myxoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E. (Cohorts A, B, E, and F)
13. Disease distribution must allow meeting with normal tissue constrains of radiation therapy. Radiation oncologist must confirm this point at local sites. (Cohort C).
14. Metastatic spread could be present in several organs (i.e., lungs and pelvic fossa) however, not all the locations have to be irradiated. (Cohort C).
15. Those lesions considered for radiation therapy have to be related to symptoms (for phase II). (Cohort C).
16. It is allowed that not all the lesions will be under radiation fields. As a general rule, the priority is to select, as target-irradiating lesions, those with greater increase in size and those largest lesions if related to symptoms. Irradiating pulmonary lesions with infiltration of pleural serosa is discouraged. (Cohort C).
17. Radiological disease progression must be documented within 6 months prior to study entry. (Cohort C)
18. Patients must have been considered eligible for systemic chemotherapy. A maximum of three previous lines in phase I and two previous lines in phase II for advanced/metastatic disease are allowed. (Cohort C).
19. The following histological subtypes can be included for the phase II part (central pathology review is mandatory before accrual): undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, angiosarcoma, epithelial hemangioendothelioma, liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cell, pleomorphic), synovial sarcoma, fibrosarcoma and its variants (epithelial fibrosarcoma/low grade fibromyxoid sarcoma), solitary fibrous tumor, malignant peripheral nerve sheath tumor (MPNST), myxofibrosarcoma, epithelioid sarcoma and (NOS) unclassified sarcoma. (Cohort C)
20. Patients must have received a previous chemotherapy line in advanced disease unless contraindicated or not indicated. (Cohorts A, B, E, and F)
21. Radiological disease progression must be documented within 6 months prior to study entry. (Cohorts A, B, E, and F.)
22. The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed. (CohortsA, B, E and F.)
23. Age: 18-75 years. (All cohorts.)
24. Measurable disease according to RECIST v1.1 criteria. (All cohorts)
25. Performance status ≤1 (ECOG).
26. Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry. (All cohorts.)
27. Patients must have a diagnosis of localized soft tissue sarcoma that lacks one or more of the following risk criteria: G3, deep and > 5 cm. At least G2 is required (i.e., G3, superficial and > 5 cm; or G3 < 5 cm deep; or G2, deep and > 5 cm, etc.). (Cohort D)
28. Patients must be diagnosed by core-biopsy and the elapsed time between biopsy and enrollment must be shorter than 6 weeks. (Cohort D)
29. Patients must be diagnosed by central pathology review with one of the following subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, synovial sarcoma, sarcoma NOS, fibrosarcoma, myxoid liposarcoma, dedifferentiated liposarcoma, solitary fibrous tumor (the formerly malignant subtype). (Cohort D)
30. Only sarcomas of limbs or trunk wall will be eligible for this cohort. (Cohort D).
31. Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point at local sites. (Cohort D).
32. Patients must have resectable primary tumor while it is allowed to enroll patients with metastatic spread that could be potentially resectable. (Cohort D)
33. Patients must have criteria of operability for the primary tumor. (Cohort D)
34. Patients must have been considered eligible for systemic chemotherapy. (Cohort D).
35. Patients have to be candidates for MRI test. (Cohort D).

Exclusion criteria 22

1. Performance status ≥ 2 (ECOG). (All cohorts)
2. Plasma bilirubin > ULN. (All cohorts).
3. Creatinine > 1.6 mg/dL. (Todas las cohortes).
4. 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. (All cohorts).
5. Patients who do not provide consent for mandatory biological samples cannot participate in the study. (All cohorts).
6. Significant cardiovascular disease (for example, dyspnea > 2 NYHA). (All cohorts).
7. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may significantly contribute to treatment toxicity. (All cohorts).
8. Uncontrolled bacterial, mycotic or viral infections. (All cohorts).
9. Women who are pregnant or breastfeeding. (All cohorts).
10. Psychological, family, social or geographic circumstances that limit the patients’ ability to comply with the protocol or informed consent. (All cohorts).
11. Patients participating in another clinical trial or receiving any other investigational product. (All cohorts).
12. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to PM14 start. (All cohorts).
13. Prior treatment with lurbinectedin, trabectedin or PM14. (All cohorts).
14. Histologies other than those described in the inclusion criteria. (Cohorts A, B, E and F).
15. Previous treatment with radiotherapy (except if previous radiotherapy treatment plus planned study radiotherapy treatment allow tissue constrains). (Cohort C).
16. Severe COPD or other severe pulmonary diseases. (Cohort C).
17. Histologies other than those described in inclusion criteria. (Cohort C).
18. High-risk localized patients are not allowed to be enrolled (those G3, deep, and larger than 5 cm or those with at least 40% risk of death by sarculator nomogram). (Cohort D).
19. Previous treatment with radiotherapy. (Cohort D)
20. Primary tumor location other than those indicated in the inclusion criteria. (Cohort D)
21. Histological subtypes other than those indicated in the inclusion criteria. (Cohort D).
22. Unresectable or inoperable primary tumor. (Cohort D)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. COHORTS A AND B Phase I: 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.
2. COHORTS E AND F Phase II: PFSR-6m (according to central radiology review): Efficacy measured by the PFSR at 6 months, which is defined as the percentage of patients who did 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.
3. COHORT C Phase I: 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.
4. COHORT C. Phase II: 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.
5. COHORT D. Phase I: 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.
6. COHORT D. Phase II: 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).

Secondary endpoints 36

1. COHORTS A AND B. Phase I. 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.
2. COHORTS A AND B. Phase I: 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).
3. COHORTS A AND B. Phase I. 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.
4. COHORTS A AND B. Phase I: Quality of life: Assessed by using the EORTC QLQ-C30 questionnaire.
5. COHORTS A AND B. Phase I: The clinical study will provide tumor and blood samples for the translational research program.
6. COHORTS A AND B. Phase I: The clinical study will provide blood samples for the measurement of PM14 concentration and baseline α-1-acid glycoprotein (AAG) levels.
7. COHORTS E AND F. Phase II: 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).
8. COHORTS E AND F. Phase II: mOS: Efficacy measured by mOS, which is defined as the median of time in months from date of enrollment to date of death due to any cause. OS will be censored on the last date a patient was known to be alive.
9. COHORTS E AND F. Phase II: Quality of life: Assessed by using the EORTC QLQ-C30 questionnaire.
10. COHORTS E AND F. Phase II: 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.
11. COHORTS E AND F. Phase II: The clinical study will provide tumor and blood samples for the translational research program.
12. COHORT C. Phase I: 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.
13. COHORT C. Phase I: 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).
14. COHORT C. PHase I: Median of progression-free survival (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.
15. COHORT C. Phase I: Quality of life: Assessed by using the EORTC QLQ-C30 questionnaire.
16. COHORT C. Phase I: The clinical study will provide tumor and blood samples for the translational research program.
17. COHORT C. Phase II: Changes in pain: Variations in pain will be measured by the Brief Pain Inventory – Short Form (BPI-SF). (Further information in the protocol)
18. COHORT C. Phase II: Changes in analgesic use: Variations in analgesic use will be measured by the Analgesic Quantification Algorithm (AQA). (More information in the protocol.)
19. COHORT C. Phase II: Changes in quality of life measured by the QLQ-C30 EORTC v3.0 questionnaire. The proportions of patients showing little (5-10 points), moderate (11-20 points) or high changes (> 20) in pain and dyspnea (and other symptoms scales if applicable) over time. • The proportions of patients showing little (5-10 points), moderate (11-20 points) or high changes (> 20) in global health status scales over time.
20. COHORT C. Phase II: 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).
21. COHORT C. Phase II: Time to progression (TTP) of irradiated nodules (according to central radiology review): TTP is defined as the time in months between the date of enrollment and the date of progression of irradiated nodules (not including deaths) (according to RECIST v1.1 criteria).
22. COHORT C. Phase II: PFSR-6m (according to central radiology review): Efficacy measured by the PFSR at 6 months, which is defined as the percentage of patients who did 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.
23. COHORT C. Phase II: mOS: Efficacy measured by mOS, which is defined as the median of time in months from date of enrollment to date of death due to any cause. OS will be censored on the last date a patient was known to be alive.
24. COHORT C. Phase II: Pathological response: Assessed using a predefined surgical specimen pathology form and method describing the precise percentage of tumor non-viable histological changes (hyalinosis, necrosis, cyst, differentiation etc) and percentage of viable tumor.
25. COHORT C. Phase II: 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.
26. COHORT C. Phase II: The clinical study will provide tumor and blood samples for the translational research program.
27. COHORT D. Phase I: 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.
28. COHORT D. Phase I: 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).
29. COHORT D. Phase I: Median of progression-free survival (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.
30. COHORT D. Phase I: Pathological response: Assessed using a predefined surgical specimen pathology form and method describing the precise percentage of tumor non-viable histological changes (hyalinosis, necrosis, cyst, differentiation etc) and percentage of viable tumor.
31. COHORT D. Phase I: The clinical study will provide tumor and blood samples for the translational research program.
32. COHORT D. Phase II: Pathological response: Assessed using a predefined surgical specimen pathology form and method describing the precise percentage of tumor non-viable histological changes (hyalinosis, necrosis, cyst, differentiation etc) and percentage of viable tumor.
33. COHORT D. Phase II: Relapse-free survival (RFS) at 3 years: Efficacy measured by RFS at 3 years, which is defined as the percentage of patients who did not experience relapse since date of surgery until year 3 after date of surgery.
34. COHORT D. Phase II: MRI imaging will be evaluated to assess variations in diffusion/perfusion parameters (exploratory).
35. COHORT D. Phase II: 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.
36. COHORT D. Phase II: The clinical study will provide tumor and blood samples for the translational research program.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Asoc Grupo Espanol De Investigacion En Sarcomas

Sponsor organisation

Asoc Grupo Espanol De Investigacion En Sarcomas

Address

Calle De Diego De Leon 47

City

Madrid

Postcode

28006

Country

Spain

Scientific contact point

Organisation

Asoc Grupo Espanol De Investigacion En Sarcomas

Contact name

Adriana Rojo

Public contact point

Organisation

Asoc Grupo Espanol De Investigacion En Sarcomas

Contact name

Adriana Rojo

Third parties 2

Locations

1 EU/EEA country · 9 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 9 files

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

Application history

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