Lung Cancer, SCLC
Conditions
Brief summary
This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a single-arm part (Phase II), in patients with recurrent SCLC who progressed after first-line platinum-based chemotherapy and who are candidates for second line therapy. No PK evaluation is planned in this study as nivolumab and ipilimumab are unlikely to alter plinabulin's PK, since the route of excretion is different.
Detailed description
This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a single arm part (Phase II), in patients with recurrent SCLC. In the Phase I part, patients will receive plinabulin at escalating doses in combination with nivolumab and ipilimumab. Doses of study drug will be administered as intravenous (IV) infusions in 21 day cycles. Patients will receive all study drugs on Day 1 of each cycle. After 4 treatment cycles, ipilimumab is stopped and patients continue treatment with nivolumab and plinabulin every 2 weeks (maintenance period) or until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs. At least 3 patients will be enrolled in each cohort, starting at 20 mg/m2 of plinabulin. The dose of plinabulin will be escalated in sequential patient cohorts after the safety data from the first cycle is reviewed. Thereafter the dose of plinabulin will be escalated to 30 mg/m2, provided that dose-limiting toxicities (DLTs) are not observed per the specified criteria, until the RP2D is determined. In the Phase II part, up to 26 patients will be treated with the triple combination of plinabulin (at RP2D) + nivolumab + ipilimumab. Patients will continue treatment until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs.
Interventions
DRUGNivolumab
A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1,PCD-1,) with immune checkpoint inhibitory and antineoplastic activities.
DRUGPlinabulin
Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally developed by Nereus Pharmaceuticals, Inc., and now by BeyondSpring Pharmaceuticals, Inc. It belongs to the diketopiperazine class of compounds with a chemical name 2, 5-piperazinedione, 3-\[\[5-(1,1-dimethylethyl)-1H-imidazol-4-yl\[methylene\]-6-(phenylmethylene)-, (3Z,6Z) (trivial name t-butyl-dehydrophenylahistin).
DRUGIpilimumab
Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Sponsors
Salma Sabbour
BeyondSpring Pharmaceuticals Inc.
Bristol-Myers Squibb
Rutgers Cancer Institute of New Jersey
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
The patients must satisfy all of the following inclusion/
Exclusion criteria
in order to be eligible for the study: * Must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines. * Males and females aged \>18 years at time of consent. * Histological or cytological confirmed extensive-stage SCLC * Patients who progressed after at least 1 platinum-based chemotherapy regimen. Patients with platinum resistance (defined as recurrence or progression of disease within 90 days of completion of the platinum-based regimen) are eligible. For phase II, patients also must have been treated with at least one prior line of PD-1/PD-L1 therapy. * Measurable disease according to RECIST v1.1 (Section 8) obtained by imaging within 28 days prior to study registration. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before registration and minimum life expectancy of at least 12 weeks. * Treatment to be initiated at least 2 weeks since last dose of prior systemic anticancer therapy (chemotherapy, radiation, and/or surgery. * Recovery to grade 1 of any clinically significant toxicity (excluding alopecia, grade 2 fatigue, vitiligo, endocrinopathies on stable replacement therapy) prior to initiation of study drugs. * Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti estrogens, or ovarian suppression. * Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within 14 days of study registration and within the 24-hour period prior to the first dose of study drug. * Sexually active women of childbearing potential enrolled in the study must agree to use 2 forms of accepted methods of contraception during the course of the study and for 23 weeks after their last dose of study drug. Effective birth control includes (a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner. * For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception as in criterion 9b above during the treatment period and for 31 weeks after the last dose of study drug. * Adequate laboratory values. * Absolute neutrophil count ≥1,000/µL * Platelet count ≥100,000/µL * Hemoglobin ≥9.0 g/dL * Total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with Gilbert's disease * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN if evidence of hepatic involvement by malignant disease) * Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥40 mL/min/1.73m2 * Lipase and Amylase ≤1.5 x ULN. Subjects with Lipase \>1.5 x ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) | Up to 42 days of first Plinabulin dose | Establish MTD of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent SCLC. MTD reflects the highest dose of plinabulin that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined in accordance to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4. |
| Progression-Free Survival (PFS) | Up to maximum of 9 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease(PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Progression Free Survival (PFS) is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to a maximum of 43 months | Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 |
| Number of Participants With Immune-related Adverse Events (irAEs) | Up to a maximum of 43 months | Assess Immune-related adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants. |
| Objective Response Rate (ORR) | Up to maximum of 9 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST1.1): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Objective Response (OR) = CR + PR |
| Clinical Benefit Rate | Up to maximum of 9 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Clinical Benefit Rate (CBR) = CR+PR+SD per RECIST v1.1. |
| Progression Free Survival at 6 Months | 6 Months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. PFS at 6 months is defined as the percentage of patient who was progression free at 6 months from the initiation of treatment. |
| Overall Survival | Up to a maximum of 45 months | Overall survival is defined as the time from treatment start until death or date of last contact. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSalma Jabbour, MD
Rutgers Cancer Institute of New Jersey
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Plinabulin 20mg/m^2 With Nivolumab and Ipilimumab On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (20mg/m2, IV) for the first 4 cycles.
After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur. | 8 |
| Plinabulin 30mg/m^2 With Nivolumab and Ipilimumab On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (30mg/m2, IV) for the first 4 cycles.
After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur. | 28 |
| Total | 36 |
Baseline characteristics
| Characteristic | Plinabulin 30mg/m^2 With Nivolumab and Ipilimumab | Total | Plinabulin 20mg/m^2 With Nivolumab and Ipilimumab |
|---|---|---|---|
| Age, Continuous | 64 years | 60 years | 56.50 years |
| Brain Metastases No | 18 Participants | 23 Participants | 5 Participants |
| Brain Metastases Yes | 10 Participants | 13 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 32 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Prior PD-L1 Prior PD-L1 = No | 1 Participants | 6 Participants | 5 Participants |
| Prior PD-L1 Prior PD-L1 = Yes | 27 Participants | 30 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 34 Participants | 8 Participants |
| Region of Enrollment United States | 28 participants | 36 participants | 8 participants |
| Sex: Female, Male Female | 12 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Male | 16 Participants | 19 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 8 | 16 / 28 |
| other Total, other adverse events | 8 / 8 | 27 / 28 |
| serious Total, serious adverse events | 4 / 8 | 21 / 28 |
Outcome results
Primary
Phase I: Maximum Tolerated Dose (MTD)
Establish MTD of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent SCLC. MTD reflects the highest dose of plinabulin that did not cause a Dose-Limiting Toxicity (DLT) in \> 33% of participants. DLTs were defined in accordance to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.
Time frame: Up to 42 days of first Plinabulin dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Phase I: Maximum Tolerated Dose (MTD) | 30 mg/m^2 |
Primary
Progression-Free Survival (PFS)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease(PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Progression Free Survival (PFS) is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.
Time frame: Up to maximum of 9 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint PFS was defined as all patients with PD-L1 inhibitor resistant recurrent SCLC treated at the plinabulin dose of 30 mg/m\^2 with Nivolumab and Ipilimumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Progression-Free Survival (PFS) | 1.6 Months |
Secondary
Clinical Benefit Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Clinical Benefit Rate (CBR) = CR+PR+SD per RECIST v1.1.
Time frame: Up to maximum of 9 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Clinical Benefit Rate was defined as all patients with PD-L1 inhibitor resistant recurrent SCLC treated at the plinabulin dose of 30 mg/m\^2. Out of 27 PD-L1 inhibitor resistant patients, only 16 were evaluable for CBR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Clinical Benefit Rate | 50 Percentage of participants |
Secondary
Number of Participants With Adverse Events
Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
Time frame: Up to a maximum of 43 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for Adverse Events was defined as all patients receiving at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Number of Participants With Adverse Events | 8 Participants |
| Plinabulin 30mg/m^2 With Nivolumab and Ipilimumab | Number of Participants With Adverse Events | 28 Participants |
Secondary
Number of Participants With Immune-related Adverse Events (irAEs)
Assess Immune-related adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4. irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.
Time frame: Up to a maximum of 43 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for Adverse Events was defined as all patients receiving at least one dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Number of Participants With Immune-related Adverse Events (irAEs) | 1 Participants |
| Plinabulin 30mg/m^2 With Nivolumab and Ipilimumab | Number of Participants With Immune-related Adverse Events (irAEs) | 3 Participants |
Secondary
Objective Response Rate (ORR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST1.1): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Objective Response (OR) = CR + PR
Time frame: Up to maximum of 9 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Objective Response Rate was defined as all patients with PD-L1 inhibitor resistant recurrent SCLC treated at the plinabulin dose of 30 mg/m\^2. Out of 27 PD-L1 inhibitor resistant patients, only 16 were evaluable for ORR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Objective Response Rate (ORR) | 6 Percentage of participants |
Secondary
Overall Survival
Overall survival is defined as the time from treatment start until death or date of last contact.
Time frame: Up to a maximum of 45 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Overall Survival was defined as all patients with PD-L1 inhibitor resistant recurrent SCLC treated at the plinabulin dose of 30 mg/m\^2 with Nivolumab and Ipilimumab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Overall Survival | 4.2 Months |
Secondary
Progression Free Survival at 6 Months
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. PFS at 6 months is defined as the percentage of patient who was progression free at 6 months from the initiation of treatment.
Time frame: 6 Months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Progression Free Survival at 6 months was defined as all patients with PD-L1 inhibitor resistant recurrent SCLC treated at the plinabulin dose of 30 mg/m\^2 with Nivolumab and Ipilimumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Dose Escalation): Nivolumab, Ipilimumab and Plinabulin | Progression Free Survival at 6 Months | 11 Percentage of participants |