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    Clinical Trial Results:
    Phase II Trial for the Treatment of Advanced Classical Kaposi’s Sarcoma with the HIV Protease Inhibitor Indinavir in Combination with Chemotherapy

    Summary
    EudraCT number
    		 2007-000567-26
    Trial protocol
    		 IT  
    Global end of trial date
    09 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CKS/IND-CX/05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01067690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto Superiore di Sanità
    Sponsor organisation address
    Viale Regina Elena 299, Rome, Italy, 00161
    Public contact
    National HIV/AIDS Research Center, National HIV/AIDS Research Center, segr-cnaids@iss.it
    Scientific contact
    National HIV/AIDS Research Center, National HIV/AIDS Research Center, segr-cnaids@iss.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical response in patients affected by advanced classical Kaposi's sarcoma (KS) (stage III/IV) treated with daily oral administration of Indinavir upon a debulking therapy based on cycles of systemic Vinblastine +/- Bleomycin, followed by a maintenance phase with Indinavir alone.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in compliance with Good Clinical Practices (CPMP/ICH/135/95). The essential documents are archived as required by the applicable regulatory requirements. The study and any amendment were reviewed by an Independent Ethics Committees or Institutional Review Boards.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    7
    From 65 to 84 years
    17
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients recruited within the cohort of patients followed by the Dermatologic Unit, Ospedale Maggiore Policlinico, Milan, Italy, and affected by advanced classical KS (stage III/IV), a rare tumor in Europe (incidence 1-9/100000, Orphanet). First subject enrolled: June 3, 2008, last subject enrolled: June 13, 2014

    Pre-assignment
    Screening details
    		 28 subjects screened for inclusion. Subjects with other tumors, severe bronchopneumopaties, nephropathies or nephrolitiasis, significant and persistent abnormal laboratory findings, therapy with immunomodulators or chemotherapy, were excluded. A wash-out from other anti-KS therapies of at least 2 weeks was required before entering the study.

    Period 1
    Period 1 title
    Induction phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single arm
    Arm description
    		 In order to assess tolerance, initially patients started Vinblastine i.v. weekly injection according to a dose escalation of 4 mg, 6 mg, and 8 mg, in association with Indinavir at the dose of 800 mg per os, 2 times/day (every 12 hours). If well tolerated, after a 3 weeks stop, patients received Vinblastine 10 mg i.v. +/- Bleomycin 15 mg i.m., every 3 weeks, always in association with the daily Indinavir administration. After the maximal response was obtained, patients received 2 additional cycles of Vinblastine +/- Bleomycin as consolidation and then stop chemotherapy, while continuing Indinavir.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg, twice a day

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg every 3 weeks

    Investigational medicinal product name
    Bleomycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    15 mg i.m. every 3 weeks

    Number of subjects in period 1
    		Single arm
    Started
    25
    Completed
    17
    Not completed
    8
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    4
         Protocol deviation
    1
    Period 2
    Period 2 title
    Manteinance phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single arm
    Arm description
    		 12 months maintenance phase with Indinavir alone scaled up to 800 mg, 3 times/day, orally, to assess clinical response on the debulked tumor (after the induction phase). If a patient dropped-out before phase completion, clinical response was censored at the time of the last disease assessment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indinavir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg, 3 times a day

    Number of subjects in period 2
    		Single arm
    Started
    17
    Completed
    12
    Not completed
    5
         Physician decision
    1
         Disease progression
    1
         Adverse event, non-fatal
    3
    Period 3
    Period 3 title
    Post-therapy follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single arm
    Arm description
    		 12 months post-therapy follow-up without any anti-KS treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Single arm
    Started
    12
    Completed
    11
    Not completed
    1
         Disease progression
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction phase
    Reporting group description
    		 Patients underwent an induction phase where daily Indinavir (800 mg x 2/die, orally) was combined together with systemic Vinblastine (10 mg intravenously) +/- Bleomycin (15 mg intramuscularly) in cycles administered every 3 weeks. After the maximal response was obtained, patients received 2 additional cycles of Vinblastine +/-Bleomycin and then stopped chemotherapy, while continuing Indinavir

    Reporting group values
    		 Induction phase Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
    Age continuous
    62.52 (8.24)
    Units: years
        arithmetic mean (standard deviation)
    		 62.52 ± 8.24 -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Single arm
    Reporting group description
    		 In order to assess tolerance, initially patients started Vinblastine i.v. weekly injection according to a dose escalation of 4 mg, 6 mg, and 8 mg, in association with Indinavir at the dose of 800 mg per os, 2 times/day (every 12 hours). If well tolerated, after a 3 weeks stop, patients received Vinblastine 10 mg i.v. +/- Bleomycin 15 mg i.m., every 3 weeks, always in association with the daily Indinavir administration. After the maximal response was obtained, patients received 2 additional cycles of Vinblastine +/- Bleomycin as consolidation and then stop chemotherapy, while continuing Indinavir.
    Reporting group title
    Single arm
    Reporting group description
    		 12 months maintenance phase with Indinavir alone scaled up to 800 mg, 3 times/day, orally, to assess clinical response on the debulked tumor (after the induction phase). If a patient dropped-out before phase completion, clinical response was censored at the time of the last disease assessment.
    Reporting group title
    Single arm
    Reporting group description
    		 12 months post-therapy follow-up without any anti-KS treatment

    Primary: Clinical response rate after the induction phase

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    End point title
    		 Clinical response rate after the induction phase [1]
    End point description
    Responders are defined as those patients that obtained a complete clinical response (CR), a partial response (PR), improved disease (ID) or a stabilized disease (SD) after the induction phase. If a patient dropped-out before induction completion, clinical response was censored at the time on last disease assessment.
    End point type
    Primary
    End point timeframe
    Induction phase (Indinavir combined with Vinblastine +/- Bleomycin)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this is a non-comparative study, which is not adequately powered for comparing groups, no formal statistical comparisons between treatment groups were done. Demographic and baseline laboratory results were summarized by group using descriptive statistics. Demographic and baseline laboratory results were summarized by group using descriptive statistics.
    End point values
    		 Single arm
    Number of subjects analysed
    22 [2]
    Units: number of responders
    22
    Notes
    [2] - 3 out of 25 pts that started induction were not evaluated for response because dropped-out too early
    No statistical analyses for this end point

    Primary: Clinical response rate after the maintenance phase

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    End point title
    		 Clinical response rate after the maintenance phase [3]
    End point description
    Responders are defined as those patients with complete clinical response (CR), partial response (PR), improved disease (ID) or a stabilized disease (SD) after the maintenance phase. If a patient dropped-out before maintenance completion, clinical response was censored at the time on last disease assessment.
    End point type
    Primary
    End point timeframe
    12-months maintenance phase
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As this is a non-comparative study, which is not adequately powered for comparing groups, no formal statistical comparisons between treatment groups were done. Demographic and baseline laboratory results were summarized by group using descriptive statistics. Demographic and baseline laboratory results were summarized by group using descriptive statistics.
    End point values
    		 Single arm
    Number of subjects analysed
    16 [4]
    Units: number of responses
    7
    Notes
    [4] - 1 of the 17 pts that completed induction dropped-out before starting maintenance for AE
    No statistical analyses for this end point

    Secondary: Response rate after the follow-up phase

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    End point title
    		 Response rate after the follow-up phase
    End point description
    Responders are those patients with a complete clinical response (CR), partial response (PR), improved disease (ID) or stable disease (SD) after the follow-up phase. If a patient dropped-out before phase completion, clinical response was censored at the time of the last disease assessment
    End point type
    Secondary
    End point timeframe
    12 months post-therapy follow-up
    End point values
    		 Single arm
    Number of subjects analysed
    7
    Units: number of responders
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole treatment phase: induction phase plus maintenance phase
    Adverse event reporting additional description
    Treatment safety was evalauted in all the 25 enrolled patients. AE occurrence was assessed at each study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Treatment phase (Induction+maintenance)
    Reporting group description
    		 All AE reported during the treatment phase (Induction+maintenance)

    Serious adverse events
    		 Treatment phase (Induction+maintenance)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 25 (28.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
    Additional description: Colon adenocarcinoma diagnosed right after treatment start. Event graded as severe and unrelated to treatment. Patient dropped-out because enrolled in violation of the exclusion criteria
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Hyposthenia of the left hemisoma
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE. Examinations did not reveal specific abnormalities. The event resolved in 24 h,was graded as mild and unrelated to study drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia and flu-like syndrome
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE. The event was graded as moderate; asthenia was considered as possibly related to study drug, while flu-like syndrome as unrelated.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fever and cough
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE. Examinations did not reveal abnormalities. The event was graded as moderate and unlikely related to study drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Paralytic ileus
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE. Examinations did not reveal specific abnormalities. The event was graded as moderate and probably related to study drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE; no specific abnormalities were found. The event was graded as moderate and unrelated to study drug
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dorsal pain
    Additional description: The patient referred to the emergency room and thus the event was classified as SAE. Examinations did not reveal specific abnormalities. The event was graded as moderate and possibly related to study drug.
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment phase (Induction+maintenance)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 25 (96.00%)
    Investigations
    LDL cholesterol increased
         subjects affected / exposed
    17 / 25 (68.00%)
         occurrences all number
    26
    Total cholesterol increased
         subjects affected / exposed
    16 / 25 (64.00%)
         occurrences all number
    16
    Leukopenia
         subjects affected / exposed
    20 / 25 (80.00%)
         occurrences all number
    37
    Haematocrit decreased
         subjects affected / exposed
    14 / 25 (56.00%)
         occurrences all number
    25
    Red blood cell count decreased
         subjects affected / exposed
    13 / 25 (52.00%)
         occurrences all number
    23
    Haemoglobin decreased
         subjects affected / exposed
    14 / 25 (56.00%)
         occurrences all number
    23
    Cylindruria hyaline and/or hyaline-granular
         subjects affected / exposed
    16 / 25 (64.00%)
         occurrences all number
    31
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 25 (24.00%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    5 / 25 (20.00%)
         occurrences all number
    8
    Gastrointestinal disorders
    Epigastric discomfort
         subjects affected / exposed
    7 / 25 (28.00%)
         occurrences all number
    11
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Musculosketal pain
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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