COMBINATION COMPRISING A NEUROTENSIN RECEPTOR BINDING COMPOUND, GEMCITABINE AND NAB-PACLITAXEL

Abstract

The present invention relates to a combination comprising a neurotensin receptor binding compound, gemcitabine and nab-paclitaxel for use for the treatment of a neurotensin receptor overexpressing tumour in a subject.

Claims

1. A method of treating a neurotensin receptor overexpressing tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a neurotensin receptor binding compound, gemcitabine and nab-paclitaxel.

2. The method of claim 1, wherein the neurotensin receptor binding compound is radiolabeled with a therapeutic radionuclide.

3. The method of claim 2, wherein the therapeutic radionuclide is selected from the group comprising consisting of .sup.177Lu, .sup.90Y, .sup.67Cu, .sup.131I, .sup.186Re, .sup.188Re, .sup.211 At, .sup.212Pb, .sup.213Bi, .sup.225 Ac, and .sup.227Th.

4. The method of claim 2, wherein the therapeutic radionuclide is .sup.177Lu or .sup.225Ac.

5. The method of claim 1, wherein the neurotensin receptor binding compound comprises a molecule of formula (i): ##STR00003## or a complex thereof.

6. The method of claim 1, wherein the neurotensin receptor binding compound is radiolabeled with .sup.225Ac.

7. The method of claim 1, wherein the neurotensin receptor binding compound is a complex of formula (ii): ##STR00004##

8. The method of claim 1, wherein the neurotensin receptor overexpressing tumour is selected in the group comprising pancreatic ductal adenocarcinoma and colorectal cancer.

9. The method of claim 1, wherein the neurotensin receptor binding compound is a NTR1 binding compound.

10. The method of claim 1, wherein the neurotensin receptor binding compound is administered in simultaneous, separate, or sequential combination with gemcitabine and nab-paclitaxel.

11. The method of claim 1, characterized in that the combination is administered to the subject according to a 28-day cycle, wherein the neurotensin receptor binding compound is administered on day 1 of the cycle and gemcitabine and nab-paclitaxel are administered on day 1, day 8 and day 15 of the cycle.

12. The method of claim 11, characterized in that the combination is administered for up to four 28-day cycles.

13. The method of claim 11, wherein gemcitabine is administered at a dose of about 1000 mg/m.sup.2 and nab-paclitaxel is administered at a dose of about 125 mg/m.sup.2.

14. The method of claim 1, wherein the radiolabeled neurotensin receptor binding compound is administered by injection IV at a dose of about 2 to 7 GBq per injection.

15. The method of claim 1, characterized in that the combination is administered to the subject according to a 28-day cycle, wherein: on day 1 of the cycle, nab-paclitaxel is administered at a dose of 125 mg/m.sup.2 in a 30 minute intravenous infusion, followed by gemcitabine at a dose of 1000 mg/m.sup.2 in a 30-minute intravenous infusion, followed by the radiolabeled neurotensin receptor binding compound at a dose of 2 to 7 GBq by injection; on day 8 (?1 day) of the cycle, nab-paclitaxel is administered at a dose of 125 mg/m.sup.2 in a 30-minute intravenous infusion, followed by gemcitabine at a dose of 1000 mg/m.sup.2 in a 30-minute intravenous infusion, and on day 15 (?1 day) of the cycle, nab-paclitaxel is administered at a dose of 125 mg/m.sup.2 in a 30 minute intravenous infusion, followed by gemcitabine at a dose of 1000 mg/m.sup.2 in a 30-minute intravenous infusion.

16. The method of claim 15, wherein on days 16 to 28 of the cycle, none of the three compounds of the combination is administered.

17. The method of claim 1, wherein the radiolabeled neurotensin receptor binding compound is administered as a unitary dosage of less than 40 MBq.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0085] FIG. 1 represents the administration schedules from groups 1 to 9.

[0086] FIG. 2 represents the tumor volume of mice bearing subcutaneous HT-29 tumors from Groups 1, 2, 3 and 4 (Group 1=dots; Group 2=squares; Group 3=triangles; and Group 4=reversed triangles), wherein Group 2 was treated with a combination according to the invention.

[0087] FIG. 3 represents the tumor volume of mice bearing subcutaneous HT29 tumors from Groups 1, 3, 8 and 9 (Group 1=dots; Group 3=black triangles; Group 8=open triangles; Group 9=reversed triangles), wherein Group 8 was treated with a combination according to the invention.

[0088] FIG. 4 represents the mean tumor volume of mice bearing subcutaneous HT29 tumors from Groups 1, 3, 4 and 5 (Group 1=dots; Group 3=triangles; Group 4=reversed triangles; and Group 5=diamonds), wherein Group 5 was treated with a combination according to the invention.

[0089] FIG. 5 represents the mean tumor volume of mice bearing subcutaneous HT29 tumors from Groups 1, 3, 6 and 7 (Group 1=black dots; Group 3=triangles; Group 6=open dots; and Group 7=squares), wherein Group 6 was treated with a combination according to the invention.

[0090] FIG. 6 represents the administration schedules from groups 1E to 7E.

[0091] FIG. 7 represents the mean tumor volume of mice bearing subcutaneous AsPC1 tumors from Groups 1E, 3E, 4E and 5E (Group 1E=black triangles; Group 3E=white triangles; Group 4E=black squares; Group 5E=open squares), wherein Group 5E was treated with a combination according to the invention.

[0092] FIG. 8 represents the mean tumor volume of mice bearing subcutaneous AsPC1 tumors from Groups 1E, 3E, 6E and 7E (Group 1E=black triangles; Group 3E=open triangles; Group 6E=open squares; Group 7E=black squares), wherein Group 6E was treated with a combination according to the invention.

[0093] FIG. 9 represents the mean tumor volume of mice bearing subcutaneous AsPC1 tumors from Groups 1E, 2E, 3E and 7E (Group 1E=black triangles; Group 3E=open triangles; Group 2E=open squares; Group 7E=black squares), wherein Group 2E was treated with a combination according to the invention.

[0094] FIG. 10 represents the dosing regimen for a clinical trial aiming at testing the combination of the invention in human subjects.

EXAMPLES

Materials & Methods

Reference Substances

[0095] Gemcitabine was dissolved in 0.9% NaCl solution to reach 20 and 30 mg/ml concentration. Abraxane was dissolved in 0.9% NaCl solution to reach 2.5 and 3.75 mg/mL final concentration.

Radiolabeling of IPN01087 With Lutetium-177

[0096] The radiolabeling procedure was performed using ammonium acetate 0.4 M containing 0.325 M gentisic acid pH 4.2 buffer and lutetium-177 (.sup.177LuCl.sub.3, ITG, specific activity >3,000 GBq/mg at calibration).

[0097] In a microtube, lutetium-177 (.sup.177LuCl.sub.3) was mixed with ammonium acetate 0.4 M containing 0.325 M gentisic acid pH 4.2 buffer (2.8? volume of lutetium-177 solution) and IPN01087 to reach a specific activity of 85 MBq/?g. The reaction mixture was incubated at +85? C. for 30 minutes using a heating system. At the end of the incubation period, the radiolabeling incorporation was assessed by reversed phase liquid chromatography and thin layer chromatography. The radiolabeling mixture was then diluted with ammonium acetate 0.4 M containing 0.325 M gentisic acid pH 4.2 buffer, 0.9% NaCl solution, and DTPA Ca(Na.sub.3) to reach the desired radioactive doses in MBq and concentrations.

Vehicles

[0098] The vehicles of Gemcitabine and Abraxane are hereafter referred to as vehicle #1. The vehicle of .sup.177Lu-IPN01087 is hereafter referred to as vehicle #2.

Example 1: Efficacy Study on Animals Induced With HT-29 Cells

Cancer Cell Line

[0099] The HT-29 cell line was established from the primary tumor of a 44-year old Caucasian female patient with colon adenocarcinoma (Fogh J et al., J. Natl. Cancer Inst. 1977 Jul. 59(1): 221-26).

Cell Culture Method

[0100] Tumor cells were grown as monolayer at 37? C. in a humidified atmosphere (5% CO2, 95% air). The culture medium was RPMI 1640 containing 2 mM L-glutamine supplemented with 10% fetal bovine serum. For experimental use, tumor cells were detached from the culture flask using accutase and neutralized by the addition of complete culture medium. The cells were counted, and viability exceeded 85% as assessed by 0.25% trypan blue exclusion assay. Two frozen pellets of HT29 tumor cells were prepared: one frozen cell pellet prepared during the in-vitro cell culture, and one frozen cell pellet prepared using the cell suspension used for tumor induction in mice.

Animals

[0101] Healthy female Swiss Nude mice (Crl:NU(Ico)-Foxn1nu), 7 weeks old at reception, were obtained from Charles River.

Tumor Induction

[0102] Tumors were induced by subcutaneous injection of 1?107 HT29 cells in 200 ?L of RPMI 1640 medium containing matrigel (50:50, v:v, ref: 356237, BD Biosciences, France) into the right flank (in the axis of the heart) of 160 animals. HT29 tumor cell implantation was performed 24 hours after a whole-body irradiation with a gamma source (2 Gy (Nude mice), 60Co, BioMep, France). The day of tumor induction was considered as the day ?11 (D-11).

Randomization

[0103] Animals were grafted with subcutaneous HT-29 tumors on D-11 and randomized on day 0 (D0) based on their individual tumor volumes. On D0, mean tumor volumes between groups were 210 to 220 mm.sup.3, and individual tumor volumes ranged from 105 mm.sup.3 up to 315 mm.sup.3. Statistical analysis showed that there was no significant difference between groups at D-6, D-4, and D0.

[0104] .sup.177Lu-IPN01087 and the reference substances were administered by intravenous injection (IV) into the caudal vein via a catheter or by intraperitoneal (IP) injection. The recommended pH formulation for IV administration is pH 4.5-8.0 and for IP administration 4.5-8.0. The administration schedules are shown in FIG. 1. The animal groups were treated as follows: [0105] Group 1 (control group): animals received twice weekly IV injection of 0.9% NaCl (vehicle #1) for a total of 6 injections combined with one weekly IV injection of a radiolabeling buffer/NaCl 0.9% solution mixture (vehicle #2) for a total of 3 injections. [0106] Group 2 (GEM-ABX+.sup.177Lu-IPN01087 @17MBq sequential combination groups): animals received twice weekly IV injection of Abraxane at 7.5 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 60 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and sequentially combined with one weekly IV injection of .sup.177Lu IPN01087 at 17 MBq/mouse (0.38 nmol/mouse), starting 24 hours after the first Abraxane and Gemcitabine injection for 3 consecutive weeks. [0107] Group 3 (GEM-ABX group): animals received twice weekly IV injection of Abraxane at 7.5 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 60 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections. [0108] Group 4 (.sup.177Lu-IPN01087 @17MBq group): animals received twice weekly IV injection of vehicle #1 for a total of 6 injections combined with one weekly IV injection of .sup.177Lu IPN01087 at 17 MBq/mouse (0.38 nmol/mouse) for 3 consecutive weeks. [0109] Group 5 (GEM-ABX+.sup.177Lu-IPN01087 @18MBq concomitant combination groups): animals received twice weekly IV injection of Abraxane at 7.5 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 60 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and concomitantly combined with one weekly IV injection of .sup.177Lu IPN01087 at 18 MBq/mouse (0.40 nmol/mouse) at the first the first Abraxane and Gemcitabine injection for 3 consecutive weeks. [0110] Group 6 (GEM-ABX+.sup.177Lu-IPN01087 @16MBq delayed combination groups): animals received twice weekly IV injection of Abraxane at 7.5 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections (treatment schedule: TWx1,5) combined with twice weekly IV injection of Gemcitabine at 60 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and combined with one weekly IV injection of .sup.177Lu IPN01087 at 16 MBq/mouse (0.36 nmol/mouse) starting 24 hours after the second injection of Gemcitabine and Abraxane for 3 consecutive weeks. [0111] Group 7 (.sup.177Lu-IPN01087 @17MBq groups): animals received twice weekly IV injection of vehicle #1 for a total of 6 injections combined with one weekly IV injection of .sup.177Lu IPN01087 at 17 MBq/mouse (0.38 nmol/mouse) starting 24 hours after the second injection of vehicle #1 for 3 consecutive weeks. [0112] Group 8 (GEM-ABX+.sup.177Lu-IPN01087 @32MBq sequential combination groups): animals received twice weekly IV injection of Abraxane at 7.5 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 60 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and combined with one weekly IV injection of .sup.177Lu IPN01087 at 32 MBq/mouse (0.69 nmol/mouse) starting 24 hours after the first injection of Gemcitabine and Abraxane for 3 consecutive weeks. [0113] Group 9 (.sup.177Lu-IPN01087 @31MBq group): animals received twice weekly IV injection of vehicle #1 for a total of 6 injections combined with one weekly IV injection of .sup.177Lu IPN01087 at 31 MBq/mouse (0.68 nmol/mouse) starting 24 hours after the first injection of vehicle #1 for 3 consecutive weeks.

[0114] 17MBq in mice is equivalent to about 4 GBq in human (human equivalent dose).

[0115] 32MBq in mice is equivalent to about 7 GBq in human (human equivalent dose).

[0116] At the time of tumor relapse (or at termination if no escape occurs), the tumor from 3 out of 8 mice from each group were collected. Tumors will be weighed, flash-frozen, and then stored at ?80? C.

[0117] The treatment efficacy was assessed in terms of the effects of the treatments on the tumor volumes of treated animals relative to control animals. The tumor volume was estimated by the formula:

[00001]$\mathrm{Tumor}\mathrm{Volume}=\frac{{\mathrm{width}}^2?\mathrm{length}}{2}$ [0118] Tumors that were palpable and not measurable using calipers were assigned a volume of 4 mm.sup.3, indicating the technical limit measure. Tumor volume of 1000 mm.sup.3 were considered to be equal to 1 g. Individual, mean, and median tumor volumes were measured.

[0119] Results are presented in FIGS. 2 to 5.

[0120] FIG. 2 shows HT-29 tumor growth in mice treated with vehicles (Group 1=dots), Gemcitabine/Abraxane (Group 3=triangles), .sup.177Lu-IPN01087 (Group 4=reversed triangles), or a sequential combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 (Group 2=squares). Vertical dotted lines indicate the end of the treatments. While Gemcitabine/Abraxane or .sup.177Lu-IPN01087 treatments produced an inhibitory effect on tumor growth as compared to the vehicles, the sequential combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 caused a greater tumor volume regression during the treatment period. The regression was stabilized up to Day-42 before relapse.

[0121] Similarly, the data shown in FIG. 3 demonstrate that a sequential combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 at a higher dose of 31 MBq (Group 8=open triangles) produced a greater and sustained regression of the tumor. The tumor regression was followed by a stabilization up to Day-52 before relapse.

[0122] FIG. 4 and FIG. 5 show the data obtained from the mice treated with a concomitant combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 (Group 5=diamonds) or a delayed sequential combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 (Group 6=open dots). Both combinations caused a sustained tumor regression when compared with the single agent treatments.

Example 2: Efficacy Study on Animals Induced With AsPC-1 Cells

Cancer Cell Line

[0123] The AsPC 1 cell line was isolated from a metastatic site (ascites) from a 62-year old female patient (Chen W H. et al., In Vitro. 1982 Jan; 18(1):24-34).

Cell Culture Method

[0124] Tumor cells were grown as monolayer at 37? C. in a humidified atmosphere (5% CO2, 95% air). The culture medium was RPMI 1640 containing 2 mM L-glutamine supplemented with 10% fetal bovine serum. For experimental use, tumor cells were detached from the culture flask using accutase and neutralized by the addition of complete culture medium. The cells were counted, and viability exceeded 85% as assessed by 0.25% trypan blue exclusion assay. Two frozen pellets of HT29 tumor cells were prepared: one frozen cell pellet prepared during the in-vitro cell culture, and one frozen cell pellet prepared using the cell suspension used for tumor induction in mice

Animals

[0125] Healthy female Swiss Nude mice (Crl:NU(Ico)-Foxn1.sup.nu), 6 weeks old at reception, were obtained from Charles River.

Tumor Induction

[0126] Tumors were induced by subcutaneous injection of 1?107 AsPC 1 cells in 200 ?L of RPMI 1640 medium containing matrigel (50:50, v:v, ref: 356237, BD Biosciences, France) into the right flank (in the axis of the heart) of 150 animals. AsPC 1 tumor cell implantation was performed 72 hours after whole-body irradiation with a gamma source (2 Gy (Nude mice), 60Co, BioMep, France).

Randomization

[0127] Animals were randomized by individual tumor volume when tumors reach a mean volume of 150-200 mm3. Sixty-four animals (64) out of 150 were randomized into eight groups of eight animals, each using Vivo Manager? software (Biosystemes, France). Homogeneity between groups were tested by an analysis of variance (ANOVA).

[0128] .sup.177Lu-IPN01087 and the reference substances were administered by intravenous injection (IV) into the caudal vein via a catheter. The recommended pH formulation for IV administration is pH 4.5-8.0. The administration schedules are shown in FIG. 6. The animal groups were treated as follows: [0129] Group 1E (control group): animals received twice weekly IV injection of 0.9% NaCl (vehicle #1) for a total of 6 injections combined with one weekly IV injection of a radiolabeling buffer/NaCl 0.9% solution mixture (vehicle #2) for a total of 3 injections [0130] Group 2E (GEM-ABX+.sup.177Lu-IPN01087 @31MBq sequential combination groups): animals received twice weekly IV injection of Abraxane at 6.25 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 50 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and sequentially combined with one weekly IV injection of .sup.177Lu IPN01087 at 31 MBq/mouse (0.68 nmol/mouse), starting 24 hours after the first Abraxane and Gemcitabine injection for 3 consecutive weeks. [0131] Group 3E (GEM-ABX group): animals received twice weekly IV injection of Abraxane at 6.25 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 50 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections. [0132] Group 4E (.sup.177Lu-IPN01087 @19MBq group): animals received twice weekly IV injection of vehicle #1 for a total of 6 injections combined with one weekly IV injection of .sup.177Lu IPN01087 at 19MBq/mouse (0.43 nmol/mouse) for 3 consecutive weeks. [0133] Group 5E (GEM-ABX+.sup.177Lu-IPN01087 @21MBq concomitant combination groups): animals received twice weekly IV injection of Abraxane at 6.25 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 50 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and concomitantly combined with one weekly IV injection of .sup.177Lu IPN01087 at 21MBq/mouse (0.45 nmol/mouse) at the first Abraxane and Gemcitabine injection for 3 consecutive weeks. [0134] Group 6E (GEM-ABX+.sup.177Lu-IPN01087 @31MBq concomitant combination groups): animals received twice weekly IV injection of Abraxane at 6.25 mg/kg for the first 3 injections and 5 mg/kg for the last 3 injections combined with twice weekly IV injection of Gemcitabine at 50 mg/kg for the first 3 injections and 40 mg/kg for the last 3 injections and concomitantly combined with one weekly IV injection of .sup.177Lu IPN01087 at 31MBq/mouse (0.7 nmol/mouse) for 3 consecutive weeks.). [0135] Group 7E (.sup.177Lu-IPN01087 @32MBq group): animals received twice weekly IV injection of vehicle #1 for a total of 6 injections combined with one weekly IV injection of .sup.177Lu IPN01087 at 32MBq/mouse (0.71 nmol/mouse) for 3 consecutive weeks.

[0136] At the time of tumor relapse (or at termination if no escape occurs), the tumor from 3 out of 8 mice from each group were collected. Tumors will be weighed, flash-frozen, and then stored at ?80? C.

[0137] The treatment efficacy was assessed in terms of the effects of the treatments on the tumor volumes of treated animals relative to control animals. The tumor volume was estimated by the formula:

[00002]$\mathrm{Tumor}\mathrm{Volume}=\frac{{\mathrm{width}}^2?\mathrm{length}}{2}$ [0138] Tumors which were palpable and not measurable using calipers were assigned a volume of 4 mm.sup.3, indicating the technical limit measure. Tumor volume of 1000 mm.sup.3 were considered to be equal to 1 g. Individual, mean and median tumor volumes were measured.

[0139] Results are presented in FIGS. 7 to 9.

[0140] FIG. 7 shows AsPC-1 tumor growth in mice treated with vehicles (Group 1E=black triangles), Gemcitabine/Abraxane (Group 3E=open triangles), .sup.177Lu-IPN01087 (Group 4E=black squares), or a concomitant combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 (Group 5E=open squares). Vertical dotted lines indicate the start and the end of treatments. While Gemcitabine/Abraxane and .sup.177Lu-IPN01087 treatment alone produced an antitumor effect when compared to the vehicles, the concomitant combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 significantly improved tumor growth control as compared to either of the single treatment.

[0141] Similarly, a concomitant combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 at a higher dose of 32MBq (Group 6E=open squares) displayed better AsPC-1 tumor growth control as compared to Gemcitabine/Abraxane (Group 3E=open triangles) and .sup.177Lu-IPN01087 (Group 7E=black squares) alone (FIG. 8).

[0142] In addition, the data shown in FIG. 9 demonstrate that a sequential combination of Gemcitabine/Abraxane and .sup.177Lu-IPN01087 at a higher dose of 31 MBq (Group 2E=open squares) displayed a better tumor growth control than Gemcitabine/Abraxane (Groupe 3E=open triangles) and .sup.177Lu-IPN01087 (Group 7E=black squares) alone.

[0143] Overall, in combination with gemcitabine and nab-paclitaxel chemotherapy regimen, the .sup.177Lu-IPN01087 radiotherapy showed improved tumor growth control and even prolonged regression in the and HT-29 colon and AsPC-1 pancreatic cancer models, respectively, compared to the chemotherapy or radiotherapy regimens alone.

Toxicity

[0144] Weight losses were observed in all groups of mice. The mean weight losses observed in the groups receiving the combination treatment (?6% to ?17%; Group 2E, 5E, and 6E) were similar to those observed in the groups receiving either Gemcitabine/Abraxane (?8% to ?11%; Groupe 3E) or .sup.177Lu-IPN01087 (?4% to ?10%, Groups 4E, and 7E) alone.

Example 3: Clinical Trial

[0145] The combination of the invention will be administered during a cycle of 28 days as follows (FIG. 10): [0146] on day 1 of each cycle: nab-paclitaxel 125 mg/m.sup.2 in a 30-40 minute intravenous (i.v.) infusion, followed by gemcitabine 1000 mg/m.sup.2 in a 30-minute i.v. infusion, followed by .sup.177Lu-IPN01087 injection at a dose predefined in each dose escalation cohort (2 GBq to 7 GBq), [0147] on day 8 (+1 day) of each cycle: nab-paclitaxel 125 mg/m.sup.2 in a 30-40 minute i.v. infusion, followed by gemcitabine 1000 mg/m.sup.2 in a 30-minute infusion, [0148] on day 15 (+1 day) of each cycle: nab-paclitaxel 125 mg/m.sup.2 in a 30-40 minute i.v. infusion, followed by gemcitabine 1000 mg/m.sup.2 in a 30-minute infusion, and [0149] on days 16 to 28 of each cycle: none of the three compounds will be administered (rest period).

[0150] Gemcitabine and nab-paclitaxel will be administered according to the SmPC or US Prescribing Information (USPI) for metastatic pancreatic adenocarcinoma: the RD of nab-paclitaxel in combination with gemcitabine is 125 mg/m.sup.2 administered i.v. over 30 minutes on days 1, 8 and 15 of each 28-day cycle. The concurrent RD of gemcitabine is 1000 mg/m.sup.2 administered i.v. over 30 minutes immediately after the completion of nab-paclitaxel administration on days 1, 8 and 15 of each 28-day cycle. Dose reduction and modifications of both gemcitabine and nab-paclitaxel will be performed according to the SmPC and USPI: Dose adjustments during treatment of pancreatic adenocarcinoma.

[0151] Up to 6 dose levels of .sup.177Lu-IPN01087 are planned to be tested: 2.0 GBq, 3.0 GBq, 4.0 GBq, 5.0 GBq, 6.0 GBq, 7.0 GBq.