A multicenter, open-label, first-in human, multiple expansion cohort, Phase 1/2 study to evaluate the safety and efficacy of DR-01 in adult subjects with large granular lymphocytic leukemia or cytotoxic lymphomas
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase I-II
PATOLOGÍA
Leucemia linfática crónica y otros SLPC, Linfoma no Hodgkin, Mieloma Múltiple y otras gammapatías, Terapia celular y T-CARs, Linfoma, Leucemia
FECHA DE APERTURA
Julio, 2023
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
18 years of age
Histologically confirmed diagnosis of lymphoma by a hematopathologist (according to the WHO 2016 classification [Swerdlow 2016]).
For Part A only, evaluable disease is acceptable.
Able to understand and comply with protocol-required study procedures and voluntarily sign a written informed consent document
For Part B2 only, evaluable by one of the following response criteria as documented during Screening: a.Subjects must have radiographically measurable disease by computed tomography (CT) or CT/positron emission tomography (CT/PET) scan defined as at least one node measuring >1.5 cm or measurable extranodal lesion of at least 1.0 cm in longest diameter to be evaluated by Lugano criteria (Cheson 2014). b.Subjects with primary cutaneous variants must have at least 1 measurable lesion that is evaluable using the Olsen criteria (Olsen 2021) or leukemic involvement that can be evaluated using a modified TPLL response criteria (Staber 2019). c.Subjects with hepatosplenic disease or other variants that do not have measurable disease by Lugano criteria (Cheson 2014) may be eligible upon discussion with the Medical Monitor if they have identifiable leukemic involvement in BM or peripheral blood (meeting the CD8+ cytotoxic phenotype definition) that can be evaluated for response using a modified TPLL response criteria (Staber 2019), or skin involvement that can be evaluated using Olsen criteria (Olsen 2021).
Prothrombin time or international normalized ratio (INR) 1.5 × ULN
Activated partial thromboplastin time 1.5 × ULN
Creatinine clearance (CrCl) 50 mL/min (using Cockcroft-Gault )
Total bilirubin 1.5 × ULN (3 × ULN if known Gilberts disease)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 × ULN (5 × ULN if malignant involvement of the liver and approval by the medical monitor)
Amylase <1.5 × ULN
Male subjects must agree to use acceptable effective method(s) of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01.
Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least one ovary, and is <1 year postmenopausal) must agree to use a highly effective method of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01.
Baseline clinical characteristics must be evaluable for disease assessment by the ECOG E5998 (Loughran 2015) response criteria
Eastern Cooperative Oncology Group (ECOG) performance status 0 2 (Oken 1982).
Must have discontinued at least one prior line of systemic therapy either due to lack or loss of response after at least 4 months of exposure or due to intolerability at any time and still require therapy.
Subjects with T-cell subtype: Pathologically diagnosed LGLL as defined in ECOG E5998 (Loughran 2015) requiring peripheral blood showing CD3+CD57+ population >400/mm3 or CD3+CD8+ population >650/mm3, and evidence for clonal expansion (e.g., TCR PCR, TCR Vbeta by flow cytometry within 12 months prior to C1D1).
Subjects with chronic lymphoproliferative disorder of NK cells (CLPD-NK) or NK cell subtype: Pathologically diagnosed LGLL requiring peripheral blood showing CD3-CD16+/CD56+ cells.
ECOG performance status 0 1 (Oken 1982).
Subjects must have failed at least one prior systemic regimen and still require therapy. If concurrent radio-chemotherapy was applied, the chemotherapy part will be considered one line of systemic therapy.
Availability of post-progression tissue sample or willingness to consent to a baseline biopsy.
Histologically confirmed diagnosis of lymphoma by a hematopathologist (according to the WHO 2016 classification [Swerdlow 2016]).
For Part A only, evaluable disease is acceptable.
Able to understand and comply with protocol-required study procedures and voluntarily sign a written informed consent document
For Part B2 only, evaluable by one of the following response criteria as documented during Screening: a.Subjects must have radiographically measurable disease by computed tomography (CT) or CT/positron emission tomography (CT/PET) scan defined as at least one node measuring >1.5 cm or measurable extranodal lesion of at least 1.0 cm in longest diameter to be evaluated by Lugano criteria (Cheson 2014). b.Subjects with primary cutaneous variants must have at least 1 measurable lesion that is evaluable using the Olsen criteria (Olsen 2021) or leukemic involvement that can be evaluated using a modified TPLL response criteria (Staber 2019). c.Subjects with hepatosplenic disease or other variants that do not have measurable disease by Lugano criteria (Cheson 2014) may be eligible upon discussion with the Medical Monitor if they have identifiable leukemic involvement in BM or peripheral blood (meeting the CD8+ cytotoxic phenotype definition) that can be evaluated for response using a modified TPLL response criteria (Staber 2019), or skin involvement that can be evaluated using Olsen criteria (Olsen 2021).
Prothrombin time or international normalized ratio (INR) 1.5 × ULN
Activated partial thromboplastin time 1.5 × ULN
Creatinine clearance (CrCl) 50 mL/min (using Cockcroft-Gault )
Total bilirubin 1.5 × ULN (3 × ULN if known Gilberts disease)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 × ULN (5 × ULN if malignant involvement of the liver and approval by the medical monitor)
Amylase <1.5 × ULN
Male subjects must agree to use acceptable effective method(s) of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01.
Female subjects of childbearing potential (postmenarcheal, has an intact uterus and at least one ovary, and is <1 year postmenopausal) must agree to use a highly effective method of contraception (as specified in Appendix D or as permitted by regional regulatory authorities) from enrollment through at least 12 months after last dose of DR-01.
Baseline clinical characteristics must be evaluable for disease assessment by the ECOG E5998 (Loughran 2015) response criteria
Eastern Cooperative Oncology Group (ECOG) performance status 0 2 (Oken 1982).
Must have discontinued at least one prior line of systemic therapy either due to lack or loss of response after at least 4 months of exposure or due to intolerability at any time and still require therapy.
Subjects with T-cell subtype: Pathologically diagnosed LGLL as defined in ECOG E5998 (Loughran 2015) requiring peripheral blood showing CD3+CD57+ population >400/mm3 or CD3+CD8+ population >650/mm3, and evidence for clonal expansion (e.g., TCR PCR, TCR Vbeta by flow cytometry within 12 months prior to C1D1).
Subjects with chronic lymphoproliferative disorder of NK cells (CLPD-NK) or NK cell subtype: Pathologically diagnosed LGLL requiring peripheral blood showing CD3-CD16+/CD56+ cells.
ECOG performance status 0 1 (Oken 1982).
Subjects must have failed at least one prior systemic regimen and still require therapy. If concurrent radio-chemotherapy was applied, the chemotherapy part will be considered one line of systemic therapy.
Availability of post-progression tissue sample or willingness to consent to a baseline biopsy.
CRITERIOS DE EXCLUSIÓN
A reactive LGL lymphocytosis to a viral infection or LGL or associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
Hepatitis B infection (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Subjects with HCV with undetectable virus after treatment are eligible.
History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II. Major cardiac abnormalities and clotting abnormalities (e.g., uncontrolled angina, unstable arrhythmias, pulmonary embolism, deep venous thrombosis, cerebrovascular accident, myocardial infarction, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis) within 6 months prior to C1D1, except for adequately treated catheter-related venous thrombosis occurring more than 1 month before C1D1.
Hemophagocytic lymphohistiocytosis (HLH); subjects with signs and symptoms of HLH must have HLH ruled out by a BM biopsy.
Electrocardiogram (ECG) QT interval corrected for heart rate (QTc) >475 msec, measured by Fridericias formula (QTcF = QT/[RR^0.33]).
Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 g (NIH 2022). Note: subjects who switch from a high dose to a dose of 30 g/day are eligible.
Use of systemic corticosteroids at prohibited dose levels within 15 days prior to C1D1 (except for prophylaxis for radiodiagnostic contrast reactions and study-defined premedication) or use of other non-biological immunosuppressive drugs within 15 days or 5 half-lives (whichever is less), prior to C1D1.
Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy).
Any other medical or psychiatric condition, or laboratory abnormality that would increase the risk associated with study participation, in the opinion of the Investigator or Medical Monitor.
Non-biologics anticancer therapy (e.g., chemotherapy, irradiation) within 14 days or 5 half-lives (whichever is less) of C1D1.
Use of biological therapies within 30 days of C1D1.
<250/mm3 neutrophils (LGLL & ANKL)
Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, peripheral neuropathy, or hematologic parameters meeting inclusion criteria).
Autologous hematopoietic stem cell transplantation (HSCT) within 40 days of C1D1, allogeneic HSCT within 90 days
Any immunosuppressive therapy for graft versus host disease (GVHD) for subjects who are post allogeneic HSCT.
Major surgery within 28 days of C1D1 (requires more than local anesthesia or plexus blockade).
<750/mm3 neutrophils (Cytotoxic lymphoma)
<50,000/mm3 thrombocytes (for HSTCL and ANKL where leukemia manifestation is common, a lower platelet count may be allowed with Medical Monitor approval)
Active systemic infection or severe localized infection requiring systemic antibiotics, antivirals or antifungals.
Active or suspected malignant central nervous system involvement.
Life-threatening, severe complications of malignancy (e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation).
Active known second malignancy with the exception of any of the following: a.Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b.Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for at least 2 years without therapeutic intervention (anti-hormonal therapy is acceptable) c.Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen (PSA) <10 ng/mL
Infection with human immunodeficiency virus (HIV) type 1 or 2 (HIV-1 or HIV-2).
Hepatitis B infection (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Subjects with HCV with undetectable virus after treatment are eligible.
History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II. Major cardiac abnormalities and clotting abnormalities (e.g., uncontrolled angina, unstable arrhythmias, pulmonary embolism, deep venous thrombosis, cerebrovascular accident, myocardial infarction, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis) within 6 months prior to C1D1, except for adequately treated catheter-related venous thrombosis occurring more than 1 month before C1D1.
Hemophagocytic lymphohistiocytosis (HLH); subjects with signs and symptoms of HLH must have HLH ruled out by a BM biopsy.
Electrocardiogram (ECG) QT interval corrected for heart rate (QTc) >475 msec, measured by Fridericias formula (QTcF = QT/[RR^0.33]).
Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 g (NIH 2022). Note: subjects who switch from a high dose to a dose of 30 g/day are eligible.
Use of systemic corticosteroids at prohibited dose levels within 15 days prior to C1D1 (except for prophylaxis for radiodiagnostic contrast reactions and study-defined premedication) or use of other non-biological immunosuppressive drugs within 15 days or 5 half-lives (whichever is less), prior to C1D1.
Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy).
Any other medical or psychiatric condition, or laboratory abnormality that would increase the risk associated with study participation, in the opinion of the Investigator or Medical Monitor.
Non-biologics anticancer therapy (e.g., chemotherapy, irradiation) within 14 days or 5 half-lives (whichever is less) of C1D1.
Use of biological therapies within 30 days of C1D1.
<250/mm3 neutrophils (LGLL & ANKL)
Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, peripheral neuropathy, or hematologic parameters meeting inclusion criteria).
Autologous hematopoietic stem cell transplantation (HSCT) within 40 days of C1D1, allogeneic HSCT within 90 days
Any immunosuppressive therapy for graft versus host disease (GVHD) for subjects who are post allogeneic HSCT.
Major surgery within 28 days of C1D1 (requires more than local anesthesia or plexus blockade).
<750/mm3 neutrophils (Cytotoxic lymphoma)
<50,000/mm3 thrombocytes (for HSTCL and ANKL where leukemia manifestation is common, a lower platelet count may be allowed with Medical Monitor approval)
Active systemic infection or severe localized infection requiring systemic antibiotics, antivirals or antifungals.
Active or suspected malignant central nervous system involvement.
Life-threatening, severe complications of malignancy (e.g., uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation).
Active known second malignancy with the exception of any of the following: a.Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b.Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for at least 2 years without therapeutic intervention (anti-hormonal therapy is acceptable) c.Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen (PSA) <10 ng/mL
Infection with human immunodeficiency virus (HIV) type 1 or 2 (HIV-1 or HIV-2).
DESCRIPCIÓN
- To evaluate the safety and tolerability of escalating doses of DR-01 in adult subjects with relapsed/refractory LGLL or cytotoxic lymphomas - To determine potential pharmacologically optimized dose/regimen(s) for DR-01 for the LGLL and cytotoxic lymphoma populations - To estimate the ORR, CR rate, and PR rate based on disease-specific response criteria
PALABRAS CLAVE
bispecific antibody, diffuse large b-cell lymphoma (dlbcl), non germinal center b-cell type, gammapatia monoclonal, leukemia, lymphocytic, lymphoma, monoclonal gammopathy, non germinal center b-cell type
