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A Multicenter Clinical Trial of Daratumumab in Combination With Gemcitabine, Dexamethasone and Cisplatin in Patients With Relapsed/Refractory CD38 Positive PTCL-NOS, Angioimmunoblastic T-cell Lymphoma AITL and Other Nodal Lymphomas of T Follicular Helper Cells Origin

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ClinicalTrials.gov Identifier: NCT04251065
Recruitment Status : Recruiting
First Posted : January 31, 2020
Last Update Posted : December 7, 2021
Sponsor:
Information provided by (Responsible Party):
Fondazione Italiana Linfomi ONLUS

Brief Summary:
FIL_Dara-GDP is a phase II, open label, multicenter clinical trial. The sponsor of this clinical trial is Fondazione Italiana Linfomi (FIL). The primary objective is to evaluate the efficacy of 4 courses of D-GDP (Daratumumab in combination with Gemcitabine, Cisplatin, Dexamethasone) in terms of complete response in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and other nodal lymphomas of T follicular helper cells (TFH cells) origin refractory/relapsed after at least one and no more than two previous lines of therapy.

Condition or disease Intervention/treatment Phase
Refractory T-Cell Lymphoma Relapsed T-Cell Lymphoma Drug: Daratumumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Prospective, multicenter, single arm, single-stage phase II trial in patients with refractory/relapsed CD38 positive PTCL-NOS, AITL and TFH with centrally assessed CD38 expression ≥ 5%.

It is expected for the current trial that D-GDP will improve the CR rate to 40% with an absolute improvement of 20%, while the toxicity rate is maintained at 30%.

Sample size: A'Hern's Single-Stage Phase II design will be used. The sample size was calculated according to the primary efficacy endpoint. Based on literature, the null hypothesis that the true proportion of CR after four courses of D-GDP is 0.20 will be tested against an alternative CR proportion of 0.40 with an absolute improvement of 0.20, considered clinically promising with the experimental treatment. Assuming a type I error rate of 5% and a power of 80% when the CR proportion is 40% overall 35 patients will be accrued. The null hypothesis will be rejected if 12 or more CR out of 35 patients are observed after four courses of D-GDP.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open Label, Multicenter Trial of Daratumumab in Combination With Gemcitabine, Dexamethasone and Cisplatin (D-GDP) in Patients With Relapsed/Refractory CD38 Positive Peripheral T-cell Lymphoma Not Otherwise Specified (PTCL-NOS), Angioimmunoblastic T-cell Lymphoma (AITL) and Other Nodal Lymphomas of TFH Cell Origin
Actual Study Start Date : September 3, 2020
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : December 1, 2024


Arm Intervention/treatment
Experimental: Daratumumab-GDP

This is an open-label, multicenter, single arm, single-stage phase II trial. After the patient signs the written informed consent the patient will enter the screening phase planning baseline assessments and a concomitant upfront confirmation of diagnosis of PTCL-NOS, AITL or nodal lymphoma of TFH cell origin and a central evaluation of immunohistochemical positivity of CD38 on bioptic material used to perform local diagnosis of relapsed disease, or that used for the more recent biopsy in the case of refractory patients. A core needle biopsy is considered sufficient for review and CD38 evaluation. Evaluation at central laboratory can be performed in bone marrow sections in those patients with only bone marrow lymphoma infiltration.

Only patients with confirmed eligible diagnosis and a percentage of CD38 positive tumor cells ≥ 5% will be considered eligible for study treatment.

The treatment consists of an induction phase and a maintenance phase.

Drug: Daratumumab

Daratumumab in combination with Gemcitabine, Dexamethasone and Cisplatin (D-GDP).

Induction phase:

4-6 courses (according to response after cycle 4 and to patient compliance) of D-GDP every 21 days pursuant to the following schedule: Daratumumab cycle 1: 8 mg/kg i.v. on day 2 and on day 9; cycle 2-6: 16 mg/kg i.v. on day 2 and day 9) Gemcitabine 1000 mg/sm i.v. day 1 and day 8 (gemcitabine on day 8 to be skipped in case of grade 3-4 toxicity) Cisplatin 75 mg/sm i.v. day 1 Dexamethasone 40 mg i.v. or po days 1-2-3-4-9 G-CSF from day 3 to 6, and from day 10 to 13 (to be prolonged if necessary)

Maintenance:

starting 28 days after the beginning of cycle 4 or 6 (or, in case of toxicity grade > 1, after toxicity is resolved) and up to 24 cycles from start of D-GDP according to the following schedule: Daratumumab 16 mg/kg single administration every 28 days.

Other Name: Darzalex




Primary Outcome Measures :
  1. Complete Response Rate (CRR) [ Time Frame: the endpoint will be assessed from the start date of therapy to the end of the first four cycles of therapy (cycles of 21 days). ]
    The Complete Response Rate is defined as the percentage of patient in Complete Remission (according to Lugano classification response Criteria). It will be assessed after the first 4 cycles of D-GDP chemotherapy. In case of early discontinuation, efficacy will be assessed at the End Of Treatment (EOT) visit. Patients without response assessment (due to whatever reason) will be considered as non-responders.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: the endpoint will be assessed from the start date of therapy to the end of the first four cycles of therapy (cycles of 21 days) and at each restaging ]
    Overall Response Rate is defined as the percentage of patients in complete remission or in partial remission (according to the Lugano 2014 criteria) after the first 4 cycles of therapy (cycles of 21 days). Patients without response assessment (due to whatever reason) will be considered as non-responders.

  2. Overall Survival (OS) [ Time Frame: The end point will be assessed from the start date of therapy up to 24 months, and from the start date of therapy to the end of the study (up to 42 months). ]
    Overall Survival, the percentage of patients alive, is defined from the start date of therapy to the date of death from any cause. Patients alive and those who are lost to follow-up at the time of the final analysis will be censored at the date of the last contact.

  3. Progression-Free Survival (PFS) [ Time Frame: The endpoint will be assessed from the start date of therapy up to 24 months and at the end of the study (up to 42 months). ]

    The length of time during and after the treatment that patients live with the disease, but it does not get worse. Progression-Free Survival (PFS) will be defined from the date of starting therapy and the date of disease progression, relapse or death from any cause.

    Responding patients, according to the Lugano classification response Criteria, and patients who are lost to follow-up will be censored at their last assessment date.


  4. Toxicity - Incidence of relevant toxicities [ Time Frame: the endpoint will be assessed from the date of starting therapy to the end of the study (up to 42 months) ]
    Incidence of relevant toxicities. Toxicities will be classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. This endpoint will be evaluated from the start date of therapy and at any time during therapy and follow-up.


Other Outcome Measures:
  1. Role of daratumumab maintenance [ Time Frame: The endpoint will be assessed at each restaging through study completion, up to 42 months. ]
    Comparison between the Complete Remission Rate (CRR), percentage of patient in complete remission, before and after maintenance therapy

  2. Role of daratumumab maintenance [ Time Frame: The endpoint will be assessed at each restaging through study completion, up to 42 months. ]

    The evaluation of the rate of conversion in Complete Remission with daratumumab maintenance therapy for patients in Partial Remission after the induction.

    With this endpoint it will be measured the number of responses that will be converted from Partial Remission (PR) to Complete Remission (CR) in those patients that after induction therapy continued the treatment with the maintenance therapy.


  3. Percentage of CD38 expression in correlation with the response to the treatment [ Time Frame: The endpoint will be assessed from the start date of therapy to the end of the first four cycle of therapy (cycles of 21 days) and at each restaging through study completion, up to 42 months. ]
    This endpoint will evaluate the correlation between intensity of CD38 expression (percentage of expression) and response to the treatment. The extent of CD38 expression evaluated by the central designed laboratory of FIL (Fondazione Italiana Linfomi) will be performed on fresh sections cut from the paraffin block (or on unstained sections), and the percentage of positive tumor cells will be scored according to Bossard C. et al as follows: 4: >75%; 3: 50-75%; 2: 25-49%; 1: 5-24%; 0: <5%. The percentage of CD38 expression will be correlated with response measured according to the Lugano 2014 criteria



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

• Histologically documented diagnosis of CD38 (cluster of differentiation 38) positive PTCL-NOS, AITL and other nodal lymphomas of TFH cell origin as defined in the 2017 edition of the World Health Organization (WHO) classification. Patients with only bone marrow involvement are eligible.

Note: Only patients with a centrally assessed percentage of CD38 positive tumor cells ≥ 5% in the relapse biopsy, or in the more recent biopsy in the case of refractory patients, will be considered eligible for protocol study treatment.

  • Age 18-70 years
  • Relapsed or refractory to one previous lines of treatment (autologous transplantation as a consolidation to the first line of therapy should not be considered a second line)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2
  • At least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan cannot be performed). Note: Patients with only bone marrow involvement are eligible
  • Adequate hematological counts defined as follows:

    • Absolute Neutrophil count (ANC) > 1.0 x 109/L unless due to bone marrow involvement by lymphoma
    • Platelet count > 100.000/mm3 unless due to bone marrow involvement by lymphoma
  • Adequate renal function defined as follows:

    - Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula)

  • Adequate hepatic function per local laboratory reference range as follows:

    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
    • Bilirubin ≤1.5 x upper limit of normal (ULN)(unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
  • Subject understands and voluntarily signs an informed consent form approved by an Independent Ethics Committee (IEC), prior to the initiation of any screening or study-specific procedures
  • Subject must be able to adhere to the study visit schedule and other protocol requirements
  • Life expectancy ≥ 3 months
  • Women must be:

    • postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months)
    • surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy),
    • completely abstinent (periodic abstinence from intercourse is not permitted) or if sexually active, be practicing two highly effective methods of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be prepared to continue birth control measures for at least 3 months after terminating treatment.
    • Women of childbearing potential must have a negative pregnancy test at screening
  • Men must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. Men must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug.
  • Male even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following:

    • practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
    • agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception)

Exclusion Criteria:

  • Histological diagnosis different from CD38 positive PTCL-NOS, AITL, and other nodal lymphomas of TFH cell origin
  • More than two lines of previous treatment (autologous stem cell transplant performed as part of consolidation to a previous line of therapy should not be considered as a line of therapy)
  • Previous treatment with Gemcitabine or Platinum based regimens; patients who received a single course of Platinum based course (i.e. DHAP) are not excluded
  • Prior therapy with monoclonal antibody anti CD38 (against cluster of differentiation 38)
  • Concomitant experimental therapy
  • Relapse after allo SCT
  • Central nervous system (CNS) involvement with lymphoma
  • Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, investigational therapy, including targeted small molecule agents within 14 days prior to the first dose of study drug
  • Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment
  • Subject is:

    • Known to be seropositive for human immunodeficiency virus (HIV)
    • Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-hepatitis B core antigen (HBc)] ± antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
    • Known to be seropositive for hepatitis C (except in the setting of a Sustained Virologic Response(SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)
  • Cardiovascular disease (NYHA class ≥2)
  • Creatinine Clearance < 40 mL/min (Cockcroft-Gault formula)
  • Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
  • Any history of other active malignancies within 3 years prior to study entry, with the exception of adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent.
  • Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
  • Evidence of any other clinically significant uncontrolled condition(s)
  • If female, the patient is pregnant or breast-feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04251065


Contacts
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Contact: Claudia Peracchio +0039 0131033154 cperacchio@filinf.it
Contact: Elena Borgo +0039 0594222688 eborgo@filinf.it

Locations
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Sponsors and Collaborators
Fondazione Italiana Linfomi ONLUS
Investigators
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Principal Investigator: Francesco Zaja S.C. Ematologia, Trieste - Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) - SC Ematologia
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Responsible Party: Fondazione Italiana Linfomi ONLUS
ClinicalTrials.gov Identifier: NCT04251065    
Other Study ID Numbers: FIL_Dara-GDP
First Posted: January 31, 2020    Key Record Dates
Last Update Posted: December 7, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Fondazione Italiana Linfomi ONLUS:
CD38 positive
relapsed/refractory Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL)
relapsed/refractory nodal lymphomas of T follicular helper (TFH) cells
Daratumumab
Gemcitabine
Dexamethasone
Cisplatin
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, T-Cell
Immunoblastic Lymphadenopathy
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Lymphadenopathy
Daratumumab
Antineoplastic Agents