Multicohort Trial of Different Schemes of PM14 in Monotherapy and in Combination with Radiotherapy in Soft Tissue Sarcomas and Other Solid Tumor

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.

Cohort A and B (Phase I, PM14 monotherapy, advanced STS): 20-25 patients approximately per cohort.

Cohort E (Phase II, PM14 monotherapy, advanced L-sarcomas): 28 patients; (Simon's two-stage Minimax design), errors: α= 0.05; β=0.80, option related to efficacy = 35% (6-month PFSR) (Sample size 15+13), success in 6-month PFSR of ≤ 15% will be considered as unacceptable (H0), and would not warrant further investigation (null hypothesis). Success in 6-month PFSR of ≥ 35% will be considered as an acceptable result warranting further investigation of the investigational drug (H1, alternative hypothesis). A total of 15 eligible and treated patients will be included in the first stage of the study. If ≤ 2 successes are observed, the trial will be stopped in this cohort with the conclusion that the experimental treatment should not be further investigated. Else (≥ 3 successes), patients will continue to be accrued until 28 eligible patients enter the study. If 8 or more successes are observed in those 28 patients, it will be concluded that the results of this trial warrant further investigation.

Cohort F (Phase II, PM14 monotherapy, other advanced sarcomas): 29 patients; (Simon's two-stage Optimal design), errors: α= 0.05; β=0.80. option related to efficacy = 30% (6-month PFSR) (Sample size 10+19), success in 6-month PFSR of ≤ 10% will be considered as unacceptable (H0), and would not warrant further investigation (null hypothesis). Success in 6-month PFSR of ≥ 30% will be considered as an acceptable result warranting further investigation of the investigational drug (H1, alternative hypothesis). A total of 10 eligible and treated patients will be included in the first stage of the study. If ≤ 1 successes are observed, the trial will be stopped in this cohort with the conclusion that the experimental treatment should not be further investigated. Else (≥ 2 successes), patients will continue to be accrued until 29 eligible patients enter the study. If 6 or more successes are observed in those 29 patients, it will be concluded that the results of this trial warrant further investigation.

Cohort C (Best scheme of PM14 plus RTP in advanced sarcoma, head \& neck, other solid tumors)

Phase I (advanced): pulmonary and/or abdominal cohort (2 dose levels), head and neck cohort (2dose levels). 25 patients approximately.

Phase II (advanced STS): errors: α=0.05; β=0.80, option related to efficacy = 50% (ORR in irradiated nodules) (Sample size 9+15), success in ORR of ≤ 25 % will be considered as unacceptable (H0), and would not warrant further investigation (null hypothesis). Success in ORR of ≥ 50% will be considered as an acceptable result warranting further investigation of the investigational drug (H1, alternative hypothesis). A total of 9 eligible and treated patients will be included in the first stage of the study. If ≤ 2 successes are observed, the trial will be stopped in this cohort with the conclusion that the investigational combination should not be further investigated. Else (≥ 3 successes), patients will continue to be accrued until 24 eligible patients enter the study. If 10 or more successes are observed in those 24 patients, it will be concluded that the results of this trial warrant further investigation.

Cohort D (Best scheme of PM14 plus RTP in localized intermediate sarcoma)

Phase I (localized sarcoma): 2 dose levels, 10 patients approximate ly. Phase II (localized "intermediate risk" STS): errors: α=0.05; β=0.80, option related to efficacy = 30% (ORR in irradiated nodules) (Sample size 10+19), success in ORR of ≤ 10% will be considered as unacceptable (H0), and would not warrant further investigation (null hypothesis). Success in ORR of ≥ 30% will be considered as an acceptable result warranting further investigation of the investigational drug (H1, alternative hypothesis). A total of 10 eligible and treated patients will be included in the first stage of the study. If ≤ 1 successes are observed, the trial will be stopped in this cohort with the conclusion that the investigational combination should not be further investigated. Else (≥ 2 successes), patients will continue to be accrued until 29 eligible patients enter the study. If 6 or more successes are observed in those 29 patients, it will be concluded that the results of this trial warrant further investigation.

Eligibility Criteria:
Inclusion Criteria:

Cohorts A, B, E, and F

1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
2. Age: 18-75 years.
3. 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.
4. A centralized diagnosis of DD liposarcoma or mixoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E.
5. A centralized diagnosis of other sarcomas includes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, 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,
6. Patients must have received a previous chemotherapy line in advanced disease unless contraindicated or not indicated.
7. Radiological disease progression must be documented within 6 months prior to study entry.
8. The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.
9. Measurable disease according to RECIST v1.1 criteria.
10. Performance status ≤1 (ECOG).
11. Adequate bone marrow function (hemoglobin \>10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients with creatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 3.0 times the ULN, total bilirubin ≤ ULN, are acceptable.
12. 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.
13. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
14. 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).
15. Patient must have a central venous catheter for PM14 treatment.

Cohort C

1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
2. Age: 18-75 years.
3. 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 inclusion to this end. For phase II part, onlysoft tissue sarcomas will be enrolled.
4. Patients must have received a previous chemotherapy line in advanced disease.
5. Disease distribution must allow meeting with normal tissue constrains of radiation therapy. Radiation oncologist must confirm this point at local sites.
6. Metastatic spread could be present in several organs (i.e. lungs and pelvic fossa) however, not all the locations have to be irradiated.
7. Those lesions considered for radiation therapy have to be related to symptoms (for phase II).
8. 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 with symptoms. Irradiating pulmonary lesions with infiltration of pleural serosa is discouraged.
9. Radiological disease progression must be documented within 6 months prior to study entry.
10. The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.
11. 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.
12. Measurable disease according to RECIST v1.1 criteria.
13. Performance status ≤1 (ECOG).
14. Adequate respiratory functions: FEV1 \> 1L; DLco \> 40% (patients with pulmonary target lesions).
15. Adequate bone marrow function (hemoglobin \> 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.
16. 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.
17. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
18. 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).
19. Patient must have a central venous catheter for PM14 treatment.

Cohort D

1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
2. Age: 18-75 years.
3. 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.).
4. Patients must be diagnosed by core-biopsy and the elapsed time between biopsy and enrollment must be shorter than 6 weeks.
5. 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).
6. Only those sarcomas of limbs or trunk wall will be eligible for this cohort.
7. Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point at local sites.
8. Patients must have resectable primary tumor while it is allowed to enroll patients with metastatic spread that could be potentially resectable.
9. Patients must have criteria of operability for the primary tumor.
10. The patient must have been considered eligible for systemic chemotherapy.
11. Measurable disease according to RECIST v1.1 criteria.
12. Patients have to be candidates for MRI test.
13. Performance status ≤ 1 (ECOG).
14. Adequate bone marrow function (hemoglobin \> 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault's formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.
15. 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.
16. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
17. It should be performed HBV and HCV serologies 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).
18. Patient must have a central venous catheter for treatment with PM14.

Exclusion Criteria:

Cohorts A, B, E, and F

1. Performance status ≥ 2 (ECOG).
2. Plasma bilirubin \> ULN.
3. Creatinine \> 1.6 mg/dL.
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.
5. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
6. Significant cardiovascular disease (for example, dyspnea \> 2 NYHA).
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.
8. Uncontrolled bacterial, mycotic or viral infections.
9. Women who are pregnant or breastfeeding.
10. Psychological, family, social or geographic circumstances that limit the patients' ability to comply with the protocol or informed consent.
11. Patients participating in another clinical trial or receiving any other investigational product.
12. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
13. Histologies other than those described in the inclusion criteria.

Cohort C

1. Previous treatment with radiotherapy (except if previous radiotherapy treatment plus planned study radiotherapy treatment allow tissue constrains).
2. Performance status ≥ 2 (ECOG).
3. Plasma bilirubin \> ULN.
4. Creatinine \> 1.6 mg/dL.
5. History of other cancer with less than 5 years free of disease with the exception ofadequately treated basal cell carcinoma or in situ cervical cancer.
6. Severe COPD or other severe pulmonary diseases.
7. Significant cardiovascular disease (for example, dyspnea \> 2 NYHA).
8. 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.
9. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
10. Uncontrolled bacterial, mycotic or viral infections.
11. Women who are pregnant or breastfeeding.
12. Psychological, family, social or geographic circumstances that limit the patients' ability to comply with the protocol or informed consent.
13. Patients participating in another clinical trial or receiving any other investigational product.
14. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
15. Histologies other than those described in inclusion criteria.

Cohort D

1. High-risk localized patients are not allowed to be enrolled (those G3, deep, and larger than 5 cm or those with risk of death at least 40% by sarculator nomogram).
2. Previous treatment with radiotherapy.
3. Primary tumor location other than those indicated in the inclusion criteria.
4. Histological subtypes other than those indicated in the inclusion criteria.
5. Unresectable or inoperable primary tumor.
6. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
7. Performance status ≥ 2 (ECOG).
8. Plasma bilirubin \> ULN.
9. Creatinine \> 1.6 mg/dL.
10. 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.
11. Significant cardiovascular disease (for example, dyspnea \> 2 NYHA).
12. 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.
13. Uncontrolled bacterial, mycotic or viral infections.
14. Women who are pregnant or breastfeeding.
15. Psychological, family, social or geographic circumstances that limit the patients' ability to comply with the protocol or informed consent.
16. Patients participating in another clinical trial or receiving any other investigational product.
17. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.