Trial Outcomes & Findings for Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Multiple Myeloma (NCT NCT02100657)

Last Updated: 2020-10-12

Results Overview

To determine the recommended dose (RD) of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (MM). To define the RD, patients will be evaluated for DLTs during the first 28-day cycle. The RD will be the highest DL at which fewer than two out of six (33%) of evaluable patients experience a DLT during the first 28-day cycle.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

39 participants

Primary outcome timeframe

After 28-day cycle

Results posted on

2020-10-12

Participant Flow

39 patients were enrolled at 7 sites in Spain and France and 36 of them were treated with the combination of plitidepsin, bortezomib (BTZ) and dexamethasone (DXM). Patients who participated between 18Jun2014-30Aug2018 (cutoff date). The first dose of the first cycle was administered on 7Jul2014 and the last cycle was administered on 25May2018

Age≥18;Consent Informed (CI) signed;Confirmed diagnosis of MM according to the Durie-Salmon criteria;Relapsed and/or refractory disease;Eastern Cooperative Oncology Group performance status (ECOG PS)≤2

Participant milestones

Participant milestones
Measure	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Cohort 1: Dose Level 1 STARTED	0	0	8
Cohort 1: Dose Level 1 COMPLETED	0	0	0
Cohort 1: Dose Level 1 NOT COMPLETED	0	0	8
Cohort 2: Dose Level 2 STARTED	4	0	0
Cohort 2: Dose Level 2 COMPLETED	0	0	0
Cohort 2: Dose Level 2 NOT COMPLETED	4	0	0
Cohort 3: Dose Level 3 STARTED	0	27	0
Cohort 3: Dose Level 3 COMPLETED	0	0	0
Cohort 3: Dose Level 3 NOT COMPLETED	0	27	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Cohort 1: Dose Level 1 Progressive disease	0	0	6
Cohort 1: Dose Level 1 Treatment-related adverse event	0	0	1
Cohort 1: Dose Level 1 Withdrawal by Subject	0	0	1
Cohort 2: Dose Level 2 Progressive disease	2	0	0
Cohort 2: Dose Level 2 Physician Decision	1	0	0
Cohort 2: Dose Level 2 Treatment-related adverse event	1	0	0
Cohort 3: Dose Level 3 Progressive disease	0	15	0
Cohort 3: Dose Level 3 Death	0	1	0
Cohort 3: Dose Level 3 Non-treatment related adverse event	0	1	0
Cohort 3: Dose Level 3 Physician Decision	0	1	0
Cohort 3: Dose Level 3 Never were treated	0	3	0
Cohort 3: Dose Level 3 Treatment-related adverse event	0	3	0
Cohort 3: Dose Level 3 Withdrawal by Subject	0	3	0

Baseline Characteristics

Study of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Patients With Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=8 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=4 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=27 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Total n=39 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=113 Participants	0 Participants n=163 Participants	0 Participants n=160 Participants	0 Participants n=483 Participants
Age, Categorical Between 18 and 65 years	2 Participants n=113 Participants	2 Participants n=163 Participants	14 Participants n=160 Participants	18 Participants n=483 Participants
Age, Categorical >=65 years	6 Participants n=113 Participants	2 Participants n=163 Participants	13 Participants n=160 Participants	21 Participants n=483 Participants
Age, Continuous	68 years n=113 Participants	67 years n=163 Participants	64 years n=160 Participants	66 years n=483 Participants
Sex: Female, Male Female	3 Participants n=113 Participants	3 Participants n=163 Participants	12 Participants n=160 Participants	18 Participants n=483 Participants
Sex: Female, Male Male	5 Participants n=113 Participants	1 Participants n=163 Participants	15 Participants n=160 Participants	21 Participants n=483 Participants
Race/Ethnicity, Customized White	8 Participants n=113 Participants	4 Participants n=163 Participants	24 Participants n=160 Participants	36 Participants n=483 Participants
Race/Ethnicity, Customized Black	0 Participants n=113 Participants	0 Participants n=163 Participants	2 Participants n=160 Participants	2 Participants n=483 Participants
Race/Ethnicity, Customized Not reported	0 Participants n=113 Participants	0 Participants n=163 Participants	1 Participants n=160 Participants	1 Participants n=483 Participants
ECOG PS PS 0	1 Participants n=113 Participants	2 Participants n=163 Participants	5 Participants n=160 Participants	8 Participants n=483 Participants
ECOG PS PS 1	6 Participants n=113 Participants	2 Participants n=163 Participants	21 Participants n=160 Participants	29 Participants n=483 Participants
ECOG PS PS 2	1 Participants n=113 Participants	0 Participants n=163 Participants	1 Participants n=160 Participants	2 Participants n=483 Participants
Multiple myeloma type at diagnosis Non-secretory	1 Participants n=113 Participants	0 Participants n=163 Participants	1 Participants n=160 Participants	2 Participants n=483 Participants
Multiple myeloma type at diagnosis Oligosecretory	0 Participants n=113 Participants	0 Participants n=163 Participants	1 Participants n=160 Participants	1 Participants n=483 Participants
Multiple myeloma type at diagnosis Secretory	7 Participants n=113 Participants	4 Participants n=163 Participants	25 Participants n=160 Participants	36 Participants n=483 Participants
Durie-Salmon stage at diagnosis Stage I	2 Participants n=113 Participants	0 Participants n=163 Participants	1 Participants n=160 Participants	3 Participants n=483 Participants
Durie-Salmon stage at diagnosis Stage II	5 Participants n=113 Participants	1 Participants n=163 Participants	6 Participants n=160 Participants	12 Participants n=483 Participants
Durie-Salmon stage at diagnosis Stage III	1 Participants n=113 Participants	3 Participants n=163 Participants	20 Participants n=160 Participants	24 Participants n=483 Participants
Best response to last prior anticancer therapy SD	2 Participants n=113 Participants	0 Participants n=163 Participants	2 Participants n=160 Participants	4 Participants n=483 Participants
Durie-Salmon subclassification at diagnosis Substage A	8 Participants n=113 Participants	3 Participants n=163 Participants	19 Participants n=160 Participants	30 Participants n=483 Participants
Durie-Salmon subclassification at diagnosis Substage B	0 Participants n=113 Participants	1 Participants n=163 Participants	8 Participants n=160 Participants	9 Participants n=483 Participants
International Staging System at diagnosis Stage I	6 Participants n=113 Participants	0 Participants n=163 Participants	8 Participants n=160 Participants	14 Participants n=483 Participants
International Staging System at diagnosis Stage II	0 Participants n=113 Participants	1 Participants n=163 Participants	5 Participants n=160 Participants	6 Participants n=483 Participants
International Staging System at diagnosis Stage III	1 Participants n=113 Participants	2 Participants n=163 Participants	7 Participants n=160 Participants	10 Participants n=483 Participants
International Staging System at diagnosis Unknown	1 Participants n=113 Participants	1 Participants n=163 Participants	7 Participants n=160 Participants	9 Participants n=483 Participants
Best response to last prior anticancer therapy PD	1 Participants n=113 Participants	0 Participants n=163 Participants	8 Participants n=160 Participants	9 Participants n=483 Participants
Best response to last prior anticancer therapy UK	0 Participants n=113 Participants	0 Participants n=163 Participants	5 Participants n=160 Participants	5 Participants n=483 Participants
Disease status with respect to last prior therapy Relapsed	2 Participants n=113 Participants	2 Participants n=163 Participants	11 Participants n=160 Participants	15 Participants n=483 Participants
Disease status with respect to last prior therapy Total refractory	6 Participants n=113 Participants	2 Participants n=163 Participants	16 Participants n=160 Participants	24 Participants n=483 Participants
Best response to last prior anticancer therapy CR	0 Participants n=113 Participants	1 Participants n=163 Participants	1 Participants n=160 Participants	2 Participants n=483 Participants
Best response to last prior anticancer therapy VGPR	2 Participants n=113 Participants	3 Participants n=163 Participants	2 Participants n=160 Participants	7 Participants n=483 Participants
Best response to last prior anticancer therapy PR	3 Participants n=113 Participants	0 Participants n=163 Participants	9 Participants n=160 Participants	12 Participants n=483 Participants
Weight	70.9 Kg n=113 Participants	65.1 Kg n=163 Participants	72.0 Kg n=160 Participants	70.8 Kg n=483 Participants
Body surface area	1.8 m^2 n=113 Participants	1.7 m^2 n=163 Participants	1.8 m^2 n=160 Participants	1.8 m^2 n=483 Participants
Time from diagnosis to first infusion	65.3 months n=113 Participants	55.8 months n=163 Participants	64.5 months n=160 Participants	64.5 months n=483 Participants
Time from last progressive disease to first infusion	1.6 months n=113 Participants	5.3 months n=163 Participants	1.6 months n=160 Participants	1.6 months n=483 Participants
Lines of prior chemotherapy	2 lines of chemotherapy n=113 Participants	2 lines of chemotherapy n=163 Participants	5 lines of chemotherapy n=160 Participants	4 lines of chemotherapy n=483 Participants
Agents of prior chemotherapy	6.5 Agents of chemotherapy n=113 Participants	5.0 Agents of chemotherapy n=163 Participants	8.0 Agents of chemotherapy n=160 Participants	7.0 Agents of chemotherapy n=483 Participants

PRIMARY outcome

Timeframe: After 28-day cycle

Population: Participants who received at least 1 dose study treatment

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Recommended Dose of Plitidepsin in Combination With Bortezomib and Dexamethasone	—	5.0 mg/m^2 of plitidepsin	—

PRIMARY outcome

Timeframe: After 28-day cycle

Population: Participants who received at least 1 dose study treatment

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Recommended Dose of Bortezomib in Combination With Plitidepsin and Dexamethasone	—	1.3 mg/m^2 of bortezomib	—

PRIMARY outcome

Timeframe: After 28-day cycle

Population: Participants who received at least 1 dose study treatment

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Recommended Dose of Dexamethasone in Combination With Plitidepsin and Bortezomib	—	40.0 mg of dexamethasone	—

PRIMARY outcome

Timeframe: After 28-day cycle

DLTs were defined as: Hematological Toxicity * Grade 3/4 neutropenia associated with fever or lasting\>7 days related to the study treatment * Grade 3/4 thrombocytopenia accompanied by grade 3/4 hemorrhage * Extensive bone marrow (BM) infiltration, DLT was defined as grade 4 thrombocytopenia with grade 3/4 hemorrhage or grade 4 neutropenia lasting \>7 days or with fever Non-hematological Toxicity * Grade 3/4 nausea and vomiting refractory to antiemetic therapy * Grade≥3 muscular Adverse events (AE) (myalgia, muscular weakness, muscle cramps, myopathy) * Grade≥3 alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) lasting more than 1 week * Grade≥3 bilirubin increase * Grade≥3 creatine phosphokinase (CPK) increase * Cardiac toxicity * Symptomatic or treatment-requiring grade ≥1 cardiac arrhythmia related to plitidepsin * Grade≥1 left ventricular systolic dysfunction related to plitidepsin * Neuropathic pain and peripheral sensory neuropathy related to BTZ

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=12 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)	2 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years

Stringent complete response (sCR) normal Free Light Chains (FLC) ratio. No clonal cells Complete response (CR) no serum/urine M-protein, no evidence of soft tissue plasmacytoma. \<5% clonal plasma cells Very good partial response (VGPR) serum and urine M-protein detectable but not electrophoresis or \>90% reduction in serum M-protein and urine M-protein \<100 mg/24h Partial response (PR) ≥50% reduction in serum M-protein and 90% reduction in 24h urine M-protein or to \<200 mg/24h. 50% reduction in size of any soft tissue plasmacytomas Minor response (MR) 25%-49% reduction of serum M-protein and 50-89% reduction of 24h urine M-protein. 25-49% reduction in size of soft tissue plasmacytomas. No increase in size or number of bone lesions Stable disease (SD) No sCR, CR, VGPR, PR, MR or PD Progressive disease (PD) 25% increase from the lowest value: serum M-protein, urine M-protein, BM plasma cell. Increase in size, new bone lesions, soft tissue plasmacytomas or serum calcium \>11.5 mg/dL

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Response According to International Myeloma Working Group Criteria sCR	1 Participants	0 Participants	1 Participants
Response According to International Myeloma Working Group Criteria CR	0 Participants	1 Participants	0 Participants
Response According to International Myeloma Working Group Criteria VGPR	1 Participants	2 Participants	0 Participants
Response According to International Myeloma Working Group Criteria PR	2 Participants	1 Participants	1 Participants
Response According to International Myeloma Working Group Criteria MR	1 Participants	1 Participants	1 Participants
Response According to International Myeloma Working Group Criteria SD≥4 months	2 Participants	1 Participants	0 Participants
Response According to International Myeloma Working Group Criteria SD<4 months	7 Participants	0 Participants	0 Participants
Response According to International Myeloma Working Group Criteria PD	4 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Response or disease progression was assessed on Day 1 of each cycle, assessed up to 4 years

Overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR) according to the International Myeloma Working Group (IMWG) criteria

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Overall Response Rate	22.2 percentage of participants Interval 6.4 to 47.6	57.1 percentage of participants Interval 18.4 to 90.1	66.7 percentage of participants Interval 9.4 to 99.2

SECONDARY outcome

Timeframe: From the date of the first documentation of response to the date of PD or further therapy or death, up to 4 years

Duration of response (DR) was analyzed for all patients in whom a response had been observed and was calculated from the date of the first documentation of response to the date of PD or further therapy or death

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=4 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=4 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=2 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Duration of Response	12.3 months Interval 1.8 to 23.9	21.0 months Interval 6.5 to 26.6	12.6 months Interval 10.8 to 14.4

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Time to Progression	2.8 months Interval 1.2 to 4.8	10.4 months Interval 1.8 to 27.6	13.6 months Interval 3.7 to 15.3

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death due to PD, up to 4 years

Time to progression (TTP) was calculated from the date of the first infusion to the date of documented PD or death due to PD.

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Time to Progression Rates At 3 months	44.4 percentage of participants Interval 21.5 to 67.4	85.7 percentage of participants Interval 59.8 to 100.0	100.0 percentage of participants Interval 100.0 to 100.0
Time to Progression Rates At 6 months	26.7 percentage of participants Interval 5.7 to 47.6	71.4 percentage of participants Interval 38.0 to 100.0	66.7 percentage of participants Interval 13.3 to 100.0
Time to Progression Rates At 12 months	13.3 percentage of participants Interval 0.0 to 30.1	35.7 percentage of participants Interval 0.0 to 74.5	66.7 percentage of participants Interval 13.3 to 100.0

SECONDARY outcome

Timeframe: from the date of the first infusion to the date of documented PD or death, up to 4 years

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Progression-free Survival	2.8 months Interval 1.2 to 4.8	10.4 months Interval 1.8 to 27.6	13.6 months Interval 3.7 to 15.3

SECONDARY outcome

Timeframe: From the date of the first infusion to the date of documented PD or death, up to 4 years

Progression-free survival (PFS) was calculated from the date of the first infusion to the date of documented PD or death (regardless of the reason), whichever comes first

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Progression-free Survival Rates At 3 months	44.4 percentage of participants Interval 21.5 to 67.4	85.7 percentage of participants Interval 59.8 to 100.0	100.0 percentage of participants Interval 100.0 to 100.0
Progression-free Survival Rates At 6 months	26.7 percentage of participants Interval 5.7 to 47.6	71.4 percentage of participants Interval 38.0 to 100.0	66.7 percentage of participants Interval 13.3 to 100.0
Progression-free Survival Rates At 12 months	13.3 percentage of participants Interval 0.0 to 30.1	35.7 percentage of participants Interval 0.0 to 74.5	66.7 percentage of participants Interval 13.3 to 100.0

SECONDARY outcome

Timeframe: From the date of first infusion to the date of documented PD or death, up to 4 years

Event-free survival (EFS) was calculated from the date of first infusion to the date of documented PD or death, but could include additional events besides death and PD that were considered of importance

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Event-free Survival	2.8 months Interval 1.2 to 4.8	10.4 months Interval 1.8 to 27.6	13.6 months Interval 3.7 to 15.3

SECONDARY outcome

Timeframe: from the date of first infusion to the date of documented PD or death, up to 4 years

Outcome measures

Outcome measures
Measure	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=18 Participants Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=7 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=3 Participants Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Event-free Survival Rates At 6 months	26.7 percentage of participants Interval 5.7 to 47.6	71.4 percentage of participants Interval 38.0 to 100.0	66.7 percentage of participants Interval 13.3 to 100.0
Event-free Survival Rates At 12 months	13.3 percentage of participants Interval 0.0 to 30.1	35.7 percentage of participants Interval 0.0 to 74.5	66.7 percentage of participants Interval 13.3 to 100.0
Event-free Survival Rates At 3 months	44.4 percentage of participants Interval 21.5 to 67.4	85.7 percentage of participants Interval 59.8 to 100.0	100.0 percentage of participants Interval 100.0 to 100.0

Adverse Events

Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg)

Serious events: 5 serious events

Other events: 8 other events

Deaths: 1 deaths

Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg)

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg)

Serious events: 12 serious events

Other events: 24 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Pharma Mar S.A.

Phone: 00 34 91846 60 00

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review
Publication restrictions are in place

Restriction type: OTHER

Measure	Plitidepsin (4 mg/m2)+BTZ (1 mg/m2)+DXM (40 mg) n=8 participants at risk Patients received plitidepsin 4 mg/m2 and BTZ 1 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (4 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=4 participants at risk Patients received plitidepsin 4 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles	Plitidepsin (5 mg/m2)+BTZ (1.3 mg/m2)+DXM (40 mg) n=24 participants at risk Patients received plitidepsin 5 mg/m2 and BTZ 1.3 mg/m2 and DXM 40 mg. DXM was administered at least one hour before the start of plitidepsin infusion, and BTZ was administered one minute after the end of the plitidepsin infusion. Patients received a maximum of eight treatment cycles
Injury, poisoning and procedural complications Femur fracture	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Injury, poisoning and procedural complications Rib fracture	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Injury, poisoning and procedural complications Spinal fracture	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) tumour pain	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	8.3% 2/24 • Number of events 2 • Participants were assessed through study completion, approximately 4 years
Cardiac disorders atrial fibrillation	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Cardiac disorders acute coronary syndrome	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Cardiac disorders cardiac failure	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Respiratory, thoracic and mediastinal disorders lung disorder	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Blood and lymphatic system disorders anaemia	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Immune system disorders hypersensitivity	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	25.0% 1/4 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Nervous system disorders spinal cord compression	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Nervous system disorders sciatica	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Gastrointestinal disorders diarrhoea	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	25.0% 1/4 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	8.3% 2/24 • Number of events 2 • Participants were assessed through study completion, approximately 4 years
Gastrointestinal disorders vomiting	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	25.0% 1/4 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Gastrointestinal disorders nausea	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	8.3% 2/24 • Number of events 2 • Participants were assessed through study completion, approximately 4 years
Renal and urinary disorders renal failure	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Musculoskeletal and connective tissue disorders bone pain	12.5% 1/8 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Musculoskeletal and connective tissue disorders musculoskeletal pain	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	25.0% 1/4 • Number of events 1 • Participants were assessed through study completion, approximately 4 years	0.00% 0/24 • Participants were assessed through study completion, approximately 4 years
Metabolism and nutrition disorders hypercalcaemia	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Infections and infestations pneumonia	12.5% 1/8 • Number of events 2 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	8.3% 2/24 • Number of events 2 • Participants were assessed through study completion, approximately 4 years
Infections and infestations respiratory tract infection	12.5% 1/8 • Number of events 3 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	8.3% 2/24 • Number of events 3 • Participants were assessed through study completion, approximately 4 years
Infections and infestations diverticulitis	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Infections and infestations escherichia infection	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Infections and infestations gastrointestinal infection	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years
Infections and infestations pneumonia pneumococcal	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 2 • Participants were assessed through study completion, approximately 4 years
Infections and infestations respiratory syncytial virus infection	0.00% 0/8 • Participants were assessed through study completion, approximately 4 years	0.00% 0/4 • Participants were assessed through study completion, approximately 4 years	4.2% 1/24 • Number of events 1 • Participants were assessed through study completion, approximately 4 years