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22 mei 2018: Bron: ARMO Biosciences

Uitgezaaide alvleesklierkanker is een van de moeilijkste vormen van kanker om te behandelen. Ook immuuntherapie is nog niet altijd succesvol. Toch lijkt immuuntherapie met AM0010 (pegilodecakin) bij sommige patiënten met uitgezaaide alvleesklierkanker succesvol.

De producent ILLY kondigt via een persbericht een wereldwijd uit te voeren fase III studie aan waarbij AM0010 wordt gegeven en vergeleken naast Folfox voor patiënten met uitgezaaide alvleesklierkanker en/of recidief na gemcitabine / gemzar. Ook in Europa doen veel ziekenhuizen mee. Zie in het studieprotocol: Study of AM0010 With FOLFOX Compared to FOLFOX Alone Second-line Tx in Pts With Metastatic Pancreatic Cancer (Sequoia)

Ook dit is een fase III studie voor alvleesklierkanker: HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer (zie ook in gerelateerde artikelen hyaluron))

AM0010 is een zogeheten Pegylated Recombinant Human Interleukin-10 medicijn waarbij dit medicijn met verschillende andere medicijnen wordt gecombineerd, zoals ook anti-PD medicijnen. 

Interleukine-10 (IL-10) stimuleert de expansie en cytotoxiciteit van tumor-infiltrerende CD8 + T-cellen en remt ontstekingscellen CD4 + T-cellen. Pegylatie verlengt de concentratie van IL-10 in het bloed zonder het immunologische profiel te veranderen.

Op basis van deze studie: Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors werd zowel in Europa als door de FDA AM0010 (pegilodecakin) als zogeheten weesmedicijn goedgekeurd.

Uit het fase I studierapport:

Fig 1.

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Spider plots indicating the change in tumor burden (according to immune-related response criteria) in (A) all patients in the dose-escalation cohorts, (B) patients with renal cell cancer (RCC) or melanoma in the dose-escalation cohorts, and (C) all patients with RCC treated at 20 μg/kg (arrows indicate ongoing response at data cutoff). (D) Tumor response in a patient with RCC and (E) delayed tumor response in a patient with RCC (arrows indicate tumors). CRC, colorectal cancer; NSCLC, non–small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma. (*) Mixed response (some lesions reduced).

Table 3.

Clinical Response

VariableNo. of Evaluable Patients (total)Best Response (duration in months)
Dose escalation, μg/kg
 1 2 (4) 1 SD (2)
 2.5 5 (6) 1 MXR (2)
 5 5 (6) 2 SDs (20 and 6)
 10 5 (6) 2 MXRs (2 and 2)
 20 5 (6) 1 PR (4), 2 MXRs (6 and 2), 1 SD (4)
 40 5 (5) 1 PR (19+)
 All patients (1 to 40 μg/kg) 27 (33) 2 PRs, 5 MXRs, 1 SD (20)
Tumor histology (escalation cohort)
 CRC 14 (16) 1 SD (20), 2 MXRs (2 and 2)
 Melanoma 4 (4) 1 PR (19+), 1 MXR (6)
 Prostate cancer 0 (1)
 NSCLC 1 (1)
 RCC 5 (6) 1 PR (4), 2 MXRs (2 and 2)
1 SD (6)
 Pancreatic cancer 2 (4) 1 SD (4)
 Ovarian cancer 1 (1) 1 SD (2)
All patients with RCC at RP2D (20 μg/kg) 15 (19) 4 PRs (2, 4, 4+, and 4+), 6 SDs (8, 6, 4, 4, 2, and 2)
ORROR (No.)RR (%)
All escalation cohorts (1 to 40 μg/kg) 2 (27) 7
All patients at active dose (20 to 40 μg/kg) 5 (24) 21
Patients with RCC at active dose (20 μg/kg) 4 (15) 27

NOTE. SD and PR according to immune-related response criteria. MXR indicates SD with ≥ one shrinking lesion. Evaluable patients had ≥ one scheduled scan during treatment. + indicates ongoing response at data cut.

Abbreviations: CRC, colorectal cancer; MXR, mixed response; NSCLC, non–small-cell lung cancer; OR, objective response; ORR, overall response rate; PR, partial response; RCC, renal cell cancer; RP2D, recommended phase II dose; SD, stable disease.

Het originele persbericht staat ook op de website van Immunology news en klik door op de links in dit persbericht voor meer informatie.

Onderaan staat abstract plus referentielijst van eerder genoemde fase I studie.

Hier de lopende studies met AM0010 die nog open staan voor nieuwe patiënten:

AM0010 in clinical trials

A Phase 1/1b clinical trial (NCT02009449) is ongoing in 350 patients with various advanced solid tumors. The study has already shown that AM0010 treatment, alone or in combination with chemotherapeutic drugs or anti-PD1 checkpoint inhibitors, such as Opdivo (nivolumab) or Keytruda (pembrolizumab), increases the number of activated killer T-cells in the blood and tumors of patients, and achieve a reduction in tumor size.

Interim data from a subgroup of 47 patients with advanced pancreatic ductal adenocarcinoma (PDAC) showed that AM0010, in combination with FOLFOX chemotherapy, was safe and more effective than AM0010 alone, with a longer overall survival rate (median overall survival of 10.2 months and one-year survival of 47 percent).

Interim data from two subgroups of patients, those with advanced NSCLC and metastatic RCC, also showed that the combination of AM0010 with either Opdivo or Keytruda induced tumor shrinkage in a greater percentage of people (high response rates) and a long-lasting decrease in tumor size (objective responses).

Based on the positive results in pancreatic cancer patients in the Phase 1b trial, the company started an open-label, pivotal, randomized, multicenter Phase 3 study (NCT02923921). This trial, now recruiting,  aims to evaluate the safety and efficacy of AM0010 in combination with FOLFOX, compared to FOLFOX alone, as second-line therapy in patients with PDAC that has progressed during or following a first-line treatment containing Gemzar (gemcitabine).

The study’s primary endpoint is to evaluate overall survival. It aims to enroll about 566 patients and is currently recruiting across the U.S., Canada, Australia, Europe, Korea, Taiwan, and the U.K.; more information is available by clicking on its trial identification number.

The study is expected to finish in 2020.

AM0010 has an acceptable tolerability profile and encouraging clinical activity in RCC. Pegylated IL-10 (AM0010) offers a potent novel and nonredundant mechanism, adding to the arsenal of clinically active immuno-oncology drugs. The direct activation of CD8+ T cells by AM0010 in the absence of immune-related AEs should enable combination with other immune therapies that block inhibitory mechanisms.

J Clin Oncol. 2016 Oct 10; 34(29): 3562–3569.
Published online 2016 Aug 15. doi:  10.1200/JCO.2016.68.1106
PMCID: PMC5657013
PMID: 27528724

Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors

Abstract

Purpose

Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010.

Patients and Methods

Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points.

Results

In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months.

Conclusion

AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

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Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology

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