Germ Cell TumorPhase 2APACHENCT03081923
Durvalumab Alone or With Tremelimumab in Refractory Germ Cell Tumors
A Phase 2 study testing Durvalumab and Tremelimumab in people with Germ Cell Tumor, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
Trial summary
Background: The prognosis of pts who have failed multiple chemotherapy (CT) regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in germ cell tumors (GCT). D is a monoclonal antibody (mAb) that inhibits the binding of PD-L1. T, an anti-CTLA4 mAb, is an immunomodulatory therapy. Read more about this study
- Who is it for?
- Ages 18 to 75 years, men only
- Conditions the study is for
- Germ Cell Tumor
- What is being tested?
- Durvalumab and Tremelimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 1 siteItaly
- Study dates
- 1 Feb 2017to 6 Dec 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Male of female gender.
- Histological or clinical diagnosis of GCT.
- Availability of archival tumor samples for local assessment (by immunohistochemistry) of PD-L1 expression.
- Either gonadal or extragonadal tumor primary.
- Failure of ≥2 prior chemotherapy regimens for metastatic disease (1-2 cycles of cisplatin, etoposide and bleomycin (PEB) or 1 cycle carboplatin area under the curve (AUC) 7 given in the adjuvant setting for clinical stage I disease will not be counted as prior lines).
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- Failure of high-dose chemotherapy will be allowed.
- Brain metastases: patients who present with brain metastases as the sole site of disease relapse/progression are not allowed to enter the study. Otherwise, patients with metastatic disease including brain metastases will be allowed provided that they have been irradiated, are stable from at least 4 weeks, and a wash-out period from steroids has occurred (28 days).
- Subjects must provide written informed consent.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Adequate end-organ system function tests.
- See the study full protocol for durvalumab-specific and tremelimumab requirements.
Who cannot join
- Prior exposure to immune-mediated therapy, including but not limited to, other anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
- Patients with Grade <2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal Investigator.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included after consultation with the Principal Investigator.
- Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.
- History of allogenic organ transplantation that requires use of immunosuppressive agents.
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- Active or prior documented autoimmune or inflammatory disorders.
- Active infection including active tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
- Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab.
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Open Label, Randomized, Phase 2 Study of the Anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, Alone or in Combination With Tremelimumab, in Patients With Advanced and Relapsed Germ Cell Tumors
Background:
The prognosis of pts who have failed multiple chemotherapy (CT) regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in germ cell tumors (GCT). D is a monoclonal antibody (mAb) that inhibits the binding of PD-L1. T, an anti-CTLA4 mAb, is an immunomodulatory therapy. Combination immunotherapy has shown improved activity compared to monotherapy. The investigators aimed to investigate the activity of D, alone or in combination with T, in chemorefractory GCT.
Read more
Trial Design:
This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles). Serum tumor markers, computed tomography and fluorodeoxyglucose positron emission tomography (FDG-PET) scans will be repeated q8 weeks. The primary endpoint is the objective response-rate (ORR=complete response or partial response with normal markers). H0: ORR rate ≤10%, H1: ORR ≥25%, type I and II error rates at 10%.
In stage 1, 11 pts will be allocated in each arm. According to Gehan's rule, the trial will be terminated whenever no response will be observed. 29 additional pts will be added to each arm fulfilling stage 1 criteria. ORR in ≥7 pts will be required. In stage 3, pts from stage 1-2 of both arms will be retrospectively evaluated for Programmed cell Death Ligand-1(PD-L1) IHC. The Ventana PD-L1 IHC assay will be used. In case of negative findings at the end of stage 2, if the target benefit is likely to occur only in PD-L1+ pts, further study prosecution in accordance with an enrichment strategy will be undertaken.
In particular, predictive power (PP) will be calculated assuming expansion of PD-L1+ cohorts up to a maximum of 60 pts. Each arm will be categorized as not promising (PP<30%) or promising (PP ≥30%). The promising one will enter the stage 3. Should both arms be judged promising, the one yielding ≥20% PP advantage will be selected; monotherapy will be preferred otherwise. Details on the algorithm to be used for PD-L1 IHC in this study will be finalized (EudraCT number 2016-001688-35).
Read the detailed description
This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles).
- Conditions
- Germ Cell Tumor
- Being tested
- Durvalumab, Tremelimumab
- Keywords
- Immunotherapy, Durvalumab, Tremelimumab, Combination therapy, Testicular cancer
- Medical subject headings
- Neoplasms, Germ Cell and Embryonal, Testicular Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabDrug
anti-PD-L1 mono therapy
TremelimumabDrug
anti-CTLA4 drug Tremelimumab mono therapy
| Study group | Role | What they receive |
|---|---|---|
| Durvalumab | Experimental | Durvalumab, 1500 mg IV, q4 weeks, until disease progression or onset of unacceptable toxicity Receives: Drug: Durvalumab |
| Duralumab and Tremelimumab | Experimental | Durvalumab, 1500 mg IV, on day 1 and q4 weeks, until disease progression or onset of unacceptable toxicity Tremelimumab, 75 mg IV, both on day 1 and q4 weeks, until disease progression or onset of unacceptable toxicity Receives: Drug: Durvalumab; Drug: Tremelimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective response-rate
Objective response-rate by computed tomography scan in accordance with the RECIST 1.1 criteria
Measured: 8 weeks
Secondary outcomes (3)
Overall survival
Number of subjects alive
Measured: 6 months
Progression-free survival
Number of subjects alive and progression-free
Measured: 3 months
Incidence of Adverse Events
Number of subjects developing side effects, graded according to the CTCAE v4.03
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Mar 2017
- Study start1 Feb 2017
- Primary completion6 Dec 2019
- Study completion6 Dec 2019
Why it stopped: loss of accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Germ Cell TumorStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Open-label, randomized, parallel arm, phase 2 trial
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- andrea necchi, MD, Principal investigator, Fondazione IRCCS Istituto Nazionale tumori - Milano
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03081923
- Sponsor's protocol ID
- INT123-16
- Acronym
- APACHE
- Status last verified
- May 2021
- First submitted
- 28 Feb 2017
- Last updated
- 14 May 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Necchi A, Giannatempo P, Raggi D, Mariani L, Colecchia M, Fare E, Monopoli F, Calareso G, Ali SM, Ross JS, Chung JH, Salvioni R. An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis. Eur Urol. 2019 Jan;75(1):201-203. doi: 10.1016/j.eururo.2018.09.010. Epub 2018 Sep 19. No abstract available.
PubMed 30243800
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label, Randomized, Phase 2 Study of the Anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, Alone or in Combination With Tremelimumab, in Patients With Advanced and Relapsed Germ Cell Tumors
- ClinicalTrials.gov ID
- NCT03081923
- Acronym / sponsor ID
- APACHE / INT123-16
- Conditions
- Germ Cell Tumor
- Keywords
- Immunotherapy, Durvalumab, Tremelimumab, Combination therapy, Testicular cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: loss of accrual
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Fondazione IRCCS Istituto Nazionale dei Tumori, MilanoUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 1 Feb 2017 (actual)
- Primary completion
- 6 Dec 2019 (actual)
- Study completion
- 6 Dec 2019 (actual)
- First posted
- 16 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
The prognosis of pts who have failed multiple chemotherapy (CT) regimens is quite dismal. PD-L1 is frequently expressed by immunohistochemistry (IHC) in germ cell tumors (GCT). D is a monoclonal antibody (mAb) that inhibits the binding of PD-L1. T, an anti-CTLA4 mAb, is an immunomodulatory therapy. Combination immunotherapy has shown improved activity compared to monotherapy. The investigators aimed to investigate the activity of D, alone or in combination with T, in chemorefractory GCT.
Trial Design:
This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles). Serum tumor markers, computed tomography and fluorodeoxyglucose positron emission tomography (FDG-PET) scans will be repeated q8 weeks. The primary endpoint is the objective response-rate (ORR=complete response or partial response with normal markers). H0: ORR rate ≤10%, H1: ORR ≥25%, type I and II error rates at 10%.
In stage 1, 11 pts will be allocated in each arm. According to Gehan's rule, the trial will be terminated whenever no response will be observed. 29 additional pts will be added to each arm fulfilling stage 1 criteria. ORR in ≥7 pts will be required. In stage 3, pts from stage 1-2 of both arms will be retrospectively evaluated for Programmed cell Death Ligand-1(PD-L1) IHC. The Ventana PD-L1 IHC assay will be used. In case of negative findings at the end of stage 2, if the target benefit is likely to occur only in PD-L1+ pts, further study prosecution in accordance with an enrichment strategy will be undertaken.
In particular, predictive power (PP) will be calculated assuming expansion of PD-L1+ cohorts up to a maximum of 60 pts. Each arm will be categorized as not promising (PP<30%) or promising (PP ≥30%). The promising one will enter the stage 3. Should both arms be judged promising, the one yielding ≥20% PP advantage will be selected; monotherapy will be preferred otherwise. Details on the algorithm to be used for PD-L1 IHC in this study will be finalized (EudraCT number 2016-001688-35).
Detailed description
This is an open-label, randomized, 3-stage, phase 2 study. Pts who have failed ≥2 prior CT regimens (including high-dose CT) will be randomized to receive one of the following: D, 1.5 g via IV infusion q4w, for up to a total of 12 months (13 doses/cycles) alone or with T, 75 mg IV q4w, starting on week 0, for up to 4 months (4 doses/cycles).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Open-label, randomized, parallel arm, phase 2 trial
| Arm | Type | Receives |
|---|---|---|
| Durvalumab | Experimental | Drug: DurvalumabDurvalumab, 1500 mg IV, q4 weeks, until disease progression or onset of unacceptable toxicity |
| Duralumab and Tremelimumab | Experimental | Drug: Durvalumab, Drug: TremelimumabDurvalumab, 1500 mg IV, on day 1 and q4 weeks, until disease progression or onset of unacceptable toxicity Tremelimumab, 75 mg IV, both on day 1 and q4 weeks, until disease progression or onset of unacceptable toxicity |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Age ≥ 18 years
- Male of female gender.
- Histological or clinical diagnosis of GCT.
- Availability of archival tumor samples for local assessment (by immunohistochemistry) of PD-L1 expression.
- Either gonadal or extragonadal tumor primary.
Key exclusion criteria (10 listed)
- Prior exposure to immune-mediated therapy, including but not limited to, other anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines.
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
- Patients with Grade <2 neuropathy will be evaluated on a case-by-case basis after consultation with the Principal Investigator.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included after consultation with the Principal Investigator.
- Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Durvalumabanti-PD-L1 mono therapy | Drug | Duralumab and Tremelimumab, Durvalumab |
| Tremelimumabanti-CTLA4 drug Tremelimumab mono therapy | Drug | Duralumab and Tremelimumab |
Primary outcome
Objective response-rate
Time frame: 8 weeks
Objective response-rate by computed tomography scan in accordance with the RECIST 1.1 criteria
3 secondary outcomes
Overall survival
Time frame: 6 months
Progression-free survival
Time frame: 3 months
Incidence of Adverse Events
Time frame: 8 weeks
Results and safety
The study was stopped early (reason given: loss of accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2021.
- Derived from this study: PubMed 30243800Necchi A, Giannatempo P, Raggi D, Mariani L, Colecchia M, Fare E, Monopoli F, Calareso G, Ali SM, Ross JS, Chung JH, Salvioni R. An Open-label Randomized Phase 2 study of Durvalumab Alone or in Combination with Tremelimumab in Patients with Advanced Germ Cell Tumors (APACHE): Results from the First Planned Interim Analysis. Eur Urol. 2019 Jan;75(1):201-203. doi: 10.1016/j.eururo.2018.09.010. Epub 2018 Sep 19. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
andrea necchi, MD principal investigator
Fondazione IRCCS Istituto Nazionale tumori - Milano
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Durvalumab and Tremelimumab in people with Germ Cell Tumor, run by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 14 May 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: loss of accrual). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response-rate (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03081923, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 May 2021.