Solid Tumor
Conditions
Keywords
immuno-oncology
Brief summary
The main purpose of this study is to evaluate the safety and tolerability of chemokine (C-X-C Motif) receptor 4 (CXCR4) peptide antagonist LY2510924 and durvalumab for phase 1a and 1b in participants with advanced refractory solid tumors.
Interventions
DRUGLY2510924
Administered SQ
DRUGDurvalumab
Administered IV
Sponsors
AstraZeneca
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Phase 1a: Have histologic or cytologic confirmation of advanced solid tumor * Have at least 1 measurable lesion assessable using standard techniques by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 * Have adequate organ function * Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale * Have provided tissue from a newly obtained core or excisional biopsy of a tumor lesion or a recent biopsy defined by ≤3 years since last documented progression of disease * Have an estimated life expectancy of ≥12 weeks, in the judgment of the investigator
Exclusion criteria
* Have a serious concomitant systemic disorder including human immunodeficiency virus (HIV), active hepatitis B virus (HBV), active HCV, active autoimmune disorder or disease requiring high dose of steroids * Have a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection or chronic diarrhea * Have evidence of interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity or active, noninfectious pneumonitis * Have an active infection requiring systemic therapy * Have had prior therapy with an anti-programmed cell death 1 (PD-1), anti-PD-L1, anti-PD-L2, or anticytotoxic T lymphocyte-associated antigen-4 antibody * Moderate or severe cardiovascular disease * Have symptomatic or uncontrolled brain metastases, spinal cord compression, or leptomeningeal disease requiring concurrent treatment * Have received a live vaccine within 30 days before the first dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | Cycle 1 (28 Days) | DLT is defined as 1 of the following adverse events(AE) reported during the Phase 1a DLT observation period,if considered to be definitely,probably,or possibly related to either study regimen by the investigator;and fulfills any 1 of the following criterion using(NCI)CTCAE version(v)4.03:Grade4 immune-related AE,Grade4 non-laboratory AE,any CTCAE Grade ≥3 QT prolongation AE,≥Grade3 colitis or noninfectious pneumonitis irrespective of duration,Grade3 immune-related AE(excluding colitis,QT prolongation,or pneumonitis) that does not downgrade to Grade2 within 3 days after onset of event despite optimal medical management including systemic corticosteroids,or does not downgrade to ≤Grade 1 or baseline within 14 days,Grade2 pneumonitis that does not resolve to ≤Grade 1 within 3 days of the initiation of maximal supportive care,including corticosteroid therapy,Grade3 toxicity lasting an extended time despite optimal supportive care and there were also laboratory abnormalities criterion. |
| Maximum Tolerated Dose (MTD) of LY2510924 | Cycle 1 (28 Days) | MTD was determined after the evaluation of Phase 1a portion of the trial. For Phase 1a, any DLT-equivalent toxicities observed in Cycle 2 and beyond were also be considered in dose escalation and determining MTD/recommended Phase 2 dose. See outcome measure number 1 for the DLT criterion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Cycle 1 Day 1: Predose, 0.5, 2, 4, 6, 8, 24-30 hours; Day 15: Predose, 0.5, 2, 4, 6, 8 hours | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC \[0-∞\]) of LY2510924 when Co-Administered with Durvalumab |
| Number of Participants With Anti-Durvalumab Antibodies When Administered in Combination With LY2510924 | Predose Cycle 1 Day 1 through 90 Day Post Treatment Follow Up (Up To 12 Months) | Number of participants with treatment-emergent positive Anti-Durvalumab antibodies was summarized by treatment group. |
| Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | Baseline through Measured Progressive Disease or Death (Up To 12 Months) | Best overall response of CR or PR was defined using RECIST v 1.1 criteria. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to \<10 mm, and normalization of tumor marker levels of non-target lesions. PR was defined as ≥30% decrease in sum of diameter(SOD) of target lesions taking as reference the baseline sum diameter. PD was defined as ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR/total number of participants)\*100. |
| Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) | Baseline through Measured Progressive Disease (Up To 12 Months) | DCR: percentage of participants with CR, PR, or SD using RECIST v 1.1 criteria. CR: disappearance of all lesions, pathological lymph node reduction in short axis to \<10 mm, and normalization of tumor marker levels of non-target lesions. PR: ≥30% decrease in sum of diameter (SOD) of target lesions taking as reference baseline sum diameter. PD: ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference smallest sum of longest diameters recorded since treatment started and an absolute increase in sum diameter ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor increase to qualify for PD. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR+SD/total number of participants)\*100. |
Participant flow
Pre-assignment details
This study was conducted in 2 parts. Phase 1a of the study consisted of a dose-escalation assessment and Phase 1b of the study included 2 expansion arms. The study was terminated after the Phase 1a part was complete. A participant completed the study if they completed at least 1 cycle.
Participants by arm
| Arm | Count |
|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab 20 milligrams (mg) LY2510924 given subcutaneously (SQ) once daily in combination with 1500 mg durvalumab given intravenously (IV) on Day 1 of each cycle (28 days). | 3 |
| 30 mg LY2510924 + 1500 mg Durvalumab 30 mg LY2510924 given SQ once daily in combination with 1500 mg durvalumab given IV on Day 1 of each cycle (28 days). | 3 |
| 40 mg LY2510924 + 1500 mg Durvalumab 40 mg LY2510924 given SQ once daily in combination with 1500 mg durvalumab given IV on Day 1 of each cycle (28 days). | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | 20 mg LY2510924 + 1500 mg Durvalumab | Total | 40 mg LY2510924 + 1500 mg Durvalumab | 30 mg LY2510924 + 1500 mg Durvalumab |
|---|---|---|---|---|
| Age, Continuous | 56.33 years STANDARD_DEVIATION 22.12 | 54.89 years STANDARD_DEVIATION 12.88 | 48.33 years STANDARD_DEVIATION 3.21 | 60.00 years STANDARD_DEVIATION 7.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 3 Participants | 9 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 3 / 3 | 1 / 3 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 1 / 3 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of LY2510924
MTD was determined after the evaluation of Phase 1a portion of the trial. For Phase 1a, any DLT-equivalent toxicities observed in Cycle 2 and beyond were also be considered in dose escalation and determining MTD/recommended Phase 2 dose. See outcome measure number 1 for the DLT criterion.
Time frame: Cycle 1 (28 Days)
Population: All phase 1a participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Maximum Tolerated Dose (MTD) of LY2510924 | 40 milligram (mg) |
Primary
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
DLT is defined as 1 of the following adverse events(AE) reported during the Phase 1a DLT observation period,if considered to be definitely,probably,or possibly related to either study regimen by the investigator;and fulfills any 1 of the following criterion using(NCI)CTCAE version(v)4.03:Grade4 immune-related AE,Grade4 non-laboratory AE,any CTCAE Grade ≥3 QT prolongation AE,≥Grade3 colitis or noninfectious pneumonitis irrespective of duration,Grade3 immune-related AE(excluding colitis,QT prolongation,or pneumonitis) that does not downgrade to Grade2 within 3 days after onset of event despite optimal medical management including systemic corticosteroids,or does not downgrade to ≤Grade 1 or baseline within 14 days,Grade2 pneumonitis that does not resolve to ≤Grade 1 within 3 days of the initiation of maximal supportive care,including corticosteroid therapy,Grade3 toxicity lasting an extended time despite optimal supportive care and there were also laboratory abnormalities criterion.
Time frame: Cycle 1 (28 Days)
Population: All participants who received at least one of dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| 30 mg LY2510924 + 1500 mg Durvalumab | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| 40 mg LY2510924 + 1500 mg Durvalumab | Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Number of Participants With Anti-Durvalumab Antibodies When Administered in Combination With LY2510924
Number of participants with treatment-emergent positive Anti-Durvalumab antibodies was summarized by treatment group.
Time frame: Predose Cycle 1 Day 1 through 90 Day Post Treatment Follow Up (Up To 12 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Number of Participants With Anti-Durvalumab Antibodies When Administered in Combination With LY2510924 | 0 Participants |
| 30 mg LY2510924 + 1500 mg Durvalumab | Number of Participants With Anti-Durvalumab Antibodies When Administered in Combination With LY2510924 | 0 Participants |
| 40 mg LY2510924 + 1500 mg Durvalumab | Number of Participants With Anti-Durvalumab Antibodies When Administered in Combination With LY2510924 | 0 Participants |
Secondary
Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)]
Best overall response of CR or PR was defined using RECIST v 1.1 criteria. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to \<10 mm, and normalization of tumor marker levels of non-target lesions. PR was defined as ≥30% decrease in sum of diameter(SOD) of target lesions taking as reference the baseline sum diameter. PD was defined as ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference the smallest sum of the longest diameters recorded since treatment started and an absolute increase in sum diameter of ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR/total number of participants)\*100.
Time frame: Baseline through Measured Progressive Disease or Death (Up To 12 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
| 30 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
| 40 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With Best Overall Response of Complete Response (CR) or Partial Response (PR) [Objective Response Rate (ORR)] | 0 percentage of participants |
Secondary
Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])
DCR: percentage of participants with CR, PR, or SD using RECIST v 1.1 criteria. CR: disappearance of all lesions, pathological lymph node reduction in short axis to \<10 mm, and normalization of tumor marker levels of non-target lesions. PR: ≥30% decrease in sum of diameter (SOD) of target lesions taking as reference baseline sum diameter. PD: ≥20% increase in SOD of target lesions and short axes of target lymph nodes, taking as reference smallest sum of longest diameters recorded since treatment started and an absolute increase in sum diameter ≥5 mm; appearance of ≥1 new lesions and/or unequivocal progression of existing non-target lesions. SD: neither sufficient shrinkage to qualify for PR nor increase to qualify for PD. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. Percentage of participants=(number of participants with CR+PR+SD/total number of participants)\*100.
Time frame: Baseline through Measured Progressive Disease (Up To 12 Months)
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) | 100 percentage of participants |
| 30 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) | 33.3 percentage of participants |
| 40 mg LY2510924 + 1500 mg Durvalumab | Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR]) | 0 percentage of participants |
Secondary
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC \[0-∞\]) of LY2510924 when Co-Administered with Durvalumab
Time frame: Cycle 1 Day 1: Predose, 0.5, 2, 4, 6, 8, 24-30 hours; Day 15: Predose, 0.5, 2, 4, 6, 8 hours
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 20 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 1 | 3390 nanogram*hour /milliliter (ng *h/mL) | Geometric Coefficient of Variation 33 |
| 20 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 15 | 1960 nanogram*hour /milliliter (ng *h/mL) | Geometric Coefficient of Variation 258 |
| 30 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 1 | 3430 nanogram*hour /milliliter (ng *h/mL) | Geometric Coefficient of Variation 17 |
| 30 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 15 | 4320 nanogram*hour /milliliter (ng *h/mL) | Geometric Coefficient of Variation 11 |
| 40 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 1 | 7490 nanogram*hour /milliliter (ng *h/mL) | Geometric Coefficient of Variation 57 |
| 40 mg LY2510924 + 1500 mg Durvalumab | Pharmacokinetics: Area Under the Concentration-Time Curve (AUC [0-∞]) of LY2510924 When Co-Administered With Durvalumab | Day 15 | NA nanogram*hour /milliliter (ng *h/mL) | — |